Red blood cell separation method

ABSTRACT

A method for centrifugally separating whole blood into red blood cells and a plasma constituent rotates about a rotational axis a separation zone having radially spaced apart walls with a high-G side and a low-G side located closer to the rotational axis than the high-G side. Whole blood enters the rotating separation zone in an entry region to begin separation. Separation is halted by a terminal wall that is circumferentially spaced from the entry region. The whole blood separates into red blood cells toward the high-G side and plasma constituent toward the low-G side. The method directs red blood cells separated in the separation zone in a circumferential flow direction toward the terminal wall. The method directs separated red blood cells from the rotating separation zone through a second path that extends, at least in part, radially beyond the high-G wall.

RELATED APPLICATION

This application is a divisional of U.S. patent application Ser. No.09/389,935 (now U.S. Pat. No. 6,524,231) filed Sep. 3, 1999 and entitled“Blood Separation Chamber with Constricted Interior Channel and RecessedPassage.”

FIELD OF THE INVENTION

This invention relates to systems and methods for processing andcollecting blood, blood constituents, or other suspensions of cellularmaterial.

BACKGROUND OF THE INVENTION

Today people routinely separate whole blood, usually by centrifugation,into its various therapeutic components, such as red blood cells,platelets, and plasma.

Conventional blood processing methods use durable centrifuge equipmentin association with single use, sterile processing systems, typicallymade of plastic. The operator loads the disposable systems upon thecentrifuge before processing and removes them afterwards.

Conventional blood centrifuges are of a size that does not permit easytransport between collection sites. Furthermore, loading and unloadingoperations can sometimes be time consuming and tedious.

In addition, a need exists for further improved systems and methods forcollecting blood components in a way that lends itself to use in highvolume, on line blood collection environments, where higher yields ofcritically needed cellular blood components, like plasma, red bloodcells, and platelets, can be realized in reasonable short processingtimes.

The operational and performance demands upon such fluid processingsystems become more complex and sophisticated, even as the demand forsmaller and more portable systems intensifies. The need therefore existsfor automated blood processing controllers that can gather and generatemore detailed information and control signals to aid the operator inmaximizing processing and separation efficiencies.

SUMMARY OF THE INVENTION

The invention provides a method for centrifugally separating whole bloodinto red blood cells and a plasma constituent. The method rotates aseparation zone about a rotational axis. The rotating separation zonehas radially spaced apart walls with a high-G side and a low-G sidelocated closer to the rotational axis than the high-G side. A blood flowpath extends circumferentially about the rotation axis. The rotatingseparation zone includes an entry region where whole blood enters therotating separation zone to begin separation and a terminal wall that iscircumferentially spaced from the entry region, where separation ishalted. The method directs whole blood into the rotating separation zonethrough a first path adjacent the entry region, to begin separation ofthe whole blood into red blood cells toward the high-G side and plasmaconstituent toward the low-G side. The method directs red blood cellsseparated in the separation zone in a circumferential flow directiontoward the terminal wall.

According to one aspect of the invention, the method directs separatedred blood cells from the rotating separation zone through a second paththat extends, at least in part, radially beyond the high-G wall.

According to another aspect of the invention, the method directsseparated red blood cells from the rotating separation zone through asecond path that is adjacent the terminal wall and that includes aportion that is recessed into the high-G wall.

According to either aspect of the invention, the method directionsplasma constituent from the rotating separation zone through a thirdpath.

Other features and advantages of the inventions are set forth in thefollowing specification and attached drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of a system that embodies features of theinvention, with the disposable processing set shown out of associationwith the processing device prior to use;

FIG. 2 is a perspective view of the system shown in FIG. 1, with thedoors to the centrifuge station and pump and valve station being shownopen to accommodate mounting of the processing set;

FIG. 3 is a perspective view of the system shown in FIG. 1 with theprocessing set fully mounted on the processing device and ready for use;

FIG. 4 is a right perspective front view of the case that houses theprocessing device shown in FIG. 1, with the lid closed for transportingthe device;

FIG. 5 is a schematic view of a blood processing circuit, which can beprogrammed to perform a variety of different blood processing proceduresin association with the device shown in FIG. 1;

FIG. 6 is an exploded perspective view of a cassette, which contains theprogrammable blood processing circuit shown in FIG. 5, and the pump andvalve station on the processing device shown in FIG. 1, which receivesthe cassette for use;

FIG. 7 is a plane view of the front side of the cassette shown in FIG.6;

FIG. 8 is an enlarged perspective view of a valve station on thecassette shown in FIG. 6;

FIG. 9 is a plane view of the back side of the cassette shown in FIG. 6;

FIG. 10 is a plane view of a universal processing set, whichincorporates the cassette shown in FIG. 6, and which can be mounted onthe device shown in FIG. 1, as shown in FIGS. 2 and 3;

FIG. 11 is a top section view of the pump and valve station in which thecassette as shown in FIG. 6 is carried for use;

FIG. 12 is a schematic view of a pneumatic manifold assembly, which ispart of the pump and valve station shown in FIG. 6, and which suppliespositive and negative pneumatic pressures to convey fluid through thecassette shown in FIGS. 7 and 9;

FIG. 13 is a perspective front view of the case that houses theprocessing device, with the lid open for use of the device, and showingthe location of various processing elements housed within the case;

FIG. 14 is a schematic view of the controller that carries out theprocess control and monitoring functions of the device shown in FIG. 1;

FIGS. 15A, 15B, and 15C are schematic side view of the blood separationchamber that the device shown in FIG. 1 incorporates, showing the plasmaand red blood cell collection tubes and the associated two in-linesensors, which detect a normal operating condition (FIG. 15A), an overspill condition (FIG. 15B), and an under spill condition (FIG. 15C);

FIG. 16 is a perspective view of a fixture that, when coupled to theplasma and red blood cell collection tubes hold the tubes in a desiredviewing alignment with the in-line sensors, as shown in FIGS. 15A, 15B,and 15C;

FIG. 17 is a perspective view of the fixture shown in FIG. 16, with aplasma cell collection tube, a red blood cell collection tube, and awhole blood inlet tube attached, gathering the tubes in an organized,side-by-side array;

FIG. 18 is a perspective view of the fixture and tubes shown in FIG. 17,as being placed into viewing alignment with the two sensors shown inFIGS. 15A, 15B, and 15C;

FIG. 19 is a schematic view of the sensing station, of which the firstand second sensors shown in FIGS. 15A, 15B, and 15C form a part;

FIG. 20 is a graph of optical densities as sensed by the first andsecond sensors plotted over time, showing an under spill condition;

FIG. 21 is an exploded top perspective view of the of a moldedcentrifugal blood processing container, which can be used in associationwith the device shown in FIG. 1;

FIG. 22 is a bottom perspective view of the molded processing containershown in FIG. 21;

FIG. 23 is a top view of the molded processing container shown in FIG.21;

FIG. 24 is a side section view of the molded processing container shownin FIG. 21, showing an umbilicus to be connected the container;

FIG. 24A is a top view of the connector that connects the umbilicus tothe molded processing container in the manner shown in FIG. 24, takengenerally along line 24A—24A in FIG. 24;

FIG. 25 is a side section view of the molded processing container shownin FIG. 24, after connection of the umbilicus to container;

FIG. 26 is an exploded, perspective view of the centrifuge station ofthe processing device shown in FIG. 1, with the processing containermounted for use;

FIG. 27 is a further exploded, perspective view of the centrifugestation and processing container shown in FIG. 26;

FIG. 28 is a side section view of the centrifuge station of theprocessing device shown in FIG. 26, with the processing containermounted for use;

FIG. 29 is a top view of a molded centrifugal blood processing containeras shown in FIGS. 21 to 23, showing a flow path arrangement forseparating whole blood into plasma and red blood cells;

FIGS. 31 to 33 are top views of molded centrifugal blood processingcontainers as shown in FIGS. 21 to 23, showing other flow patharrangements for separating whole blood into plasma and red blood cells;

FIG. 34 is a schematic view of another blood processing circuit, whichcan be programmed to perform a variety of different blood processingprocedures in association with the device shown in FIG. 1;

FIG. 35 is plane view of the front side of a cassette, which containsthe programmable blood processing circuit shown in FIG. 34;

FIG. 36 is a plane view of the back side of the cassette shown in FIG.35;

FIGS. 37A to 37E are schematic views of the blood processing circuitshown in FIG. 34, showing the programming of the cassette to carry outdifferent fluid flow tasks in connection with processing whole bloodinto plasma and red blood cells;

FIGS. 38A and 38B are schematic views of the blood processing circuitshown in FIG. 34, showing the programming of the cassette to carry outfluid flow tasks in connection with on-line transfer of an additivesolution into red blood cells separated from whole blood;

FIGS. 39A and 39B are schematic views of the blood processing circuitshown in FIG. 34, showing the programming of the cassette to carry outfluid flow tasks in connection with on-line transfer of red blood cellsseparated from whole blood through a filter to remove leukocytes;

FIG. 40 is a representative embodiment of a weigh scale suited for usein association with the device shown in FIG. 1;

FIG. 41 is a representative embodiment of another weigh suited for usein association with the device shown in FIG. 1;

FIG. 42 is a schematic view of flow rate sensing and control system fora pneumatic pump chamber employing an electrode to create an electricalfield inside the pump chamber; and

FIG. 43 is a schematic view of a pneumatic manifold assembly, which ispart of the pump and valve station shown in FIG. 6, and which suppliespositive and negative pneumatic pressures to convey fluid through thecassette shown in FIGS. 35 and 36.

The invention may be embodied in several forms without departing fromits spirit or essential characteristics. The scope of the invention isdefined in the appended claims, rather than in the specific descriptionpreceding them. All embodiments that fall within the meaning and rangeof equivalency of the claims are therefore intended to be embraced bythe claims.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

FIG. 1 shows a fluid processing system 10 that embodies the features ofthe invention. The system 10 can be used for processing various fluids.The system 10 is particularly well suited for processing whole blood andother suspensions of biological cellular materials. Accordingly, theillustrated embodiment shows the system 10 used for this purpose.

I. System Overview

The system 10 includes three principal components. These are (i) aliquid and blood flow set 12; (ii) a blood processing device 14 thatinteracts with the flow set 12 to cause separation and collection of oneor more blood components; and (iii) a controller 16 that governs theinteraction to perform a blood processing and collection procedureselected by the operator.

The blood processing device 14 and controller 16 are intended to bedurable items capable of long term use. In the illustrated and preferredembodiment, the blood processing device 14 and controller 16 are mountedinside a portable housing or case 36. The case 36 presents a compactfootprint, suited for set up and operation upon a table top or otherrelatively small surface. The case 36 is also intended to be transportedeasily to a collection site.

The case 36 includes a base 38 and a hinged lid 40, which opens (as FIG.1 shows) and closes (as FIG. 4 shows). The lid 40 includes a latch 42,for releasably locking the lid 40 closed. The lid 40 also includes ahandle 44, which the operator can grasp for transporting the case 36when the lid 40 is closed. In use, the base 38 is intended to rest in agenerally horizontal support surface.

The case 36 can be formed into a desired configuration, e.g., bymolding. The case 36 is preferably made from a lightweight, yet durable,plastic material.

The flow set 12 is intended to be a sterile, single use, disposableitem. As FIG. 2 shows, before beginning a given blood processing andcollection procedure, the operator loads various components of the flowset 12 in the case 36 in association with the device 14. The controller16 implements the procedure based upon preset protocols, taking intoaccount other input from the operator. Upon completing the procedure,the operator removes the flow set 12 from association with the device14. The portion of the set 12 holding the collected blood component orcomponents are removed from the case 36 and retained for storage,transfusion, or further processing. The remainder of the set 12 isremoved from the case 36 and discarded.

The flow set 12 shown in FIG. 1 includes a blood processing chamber 18designed for use in association with a centrifuge. Accordingly, as FIG.2 shows, the processing device 14 includes a centrifuge station 20,which receives the processing chamber 18 for use. As FIGS. 2 and 3 show,the centrifuge station 20 comprises a compartment formed in the base 38.The centrifuge station 20 includes a door 22, which opens and closes thecompartment. The door 22 opens to allow loading of the processingchamber 18. The door 22 closes to enclose the processing chamber 18during operation.

The centrifuge station 20 rotates the processing chamber 18. Whenrotated, the processing chamber 18 centrifugally separates whole bloodreceived from a donor into component parts, e.g., red blood cells,plasma, and buffy coat comprising platelets and leukocytes.

It should also be appreciated that the system 10 need not separate bloodcentrifugally. The system 10 can accommodate other types of bloodseparation devices, e.g., a membrane blood separation device.

II. The Programmable Blood Processing Circuit

The set 12 defines a programmable blood processing circuit 46. Variousconfigurations are possible. FIG. 5 schematically shows onerepresentative configuration. FIG. 34 schematically shows anotherrepresentative configuration, which will be described later.

Referring to FIG. 5, the circuit 46 can be programmed to perform avariety of different blood processing procedures in which, e.g., redblood cells are collected, or plasma is collected, or both plasma andred blood cells are collected, or the buffy coat is collected.

The circuit 46 includes several pump stations PP (N) which areinterconnected by a pattern of fluid flow paths F(N) through an array ofin line valves V(N). The circuit is coupled to the remainder of theblood processing set by ports P(N).

The circuit 46 includes a programmable network of flow paths, comprisingeleven universal ports P1 to P8 and P11 to P13 and three universal pumpstations PP1, PP2, and PP3. By selective operation of the in line valvesV1 to V14, V16 to V18, and V21 to 23, any universal port P1 to P8 andP11 to P13 can be placed in flow communication with any universal pumpstation PP1, PP2, and PP3. By selective operation of the universalvalves, fluid flow can be directed through any universal pump station ina forward direction or reverse direction between two valves, or anin-out direction through a single valve.

In the illustrated embodiment, the circuit also includes an isolatedflow path comprising two ports P9 and P10 and one pump station PP4. Theflow path is termed “isolated,” because it cannot be placed into directflow communication with any other flow path in the circuit 46 withoutexterior tubing. By selective operation of the in line valves V15, V19,and V20, fluid flow can be directed through the pump station in aforward direction or reverse direction between two valves, or an in-outdirection through a single valve.

The circuit 46 can be programmed to assigned dedicated pumping functionsto the various pump stations. For example, in a preferrred embodiment,the universal pump station PP3 can serve as a general purpose, donorinterface pump, regardless of the particular blood procedure performed,to either draw blood from the donor or return blood to the donor throughthe port P8. In this arrangement, the pump station PP4 can serve as adedicated anticoagulant pump, to draw anticoagulant from a sourcethrough the port P10 and to meter anticoagulant into the blood throughport P9.

In this arrangement, the universal pump station PP1 can serve,regardless of the particular blood processing procedure performed, as adedicated in-process whole blood pump, to convey whole blood into theblood separator. This dedicated function frees the donor interface pumpPP3 from the added function of supplying whole blood to the bloodseparator. Thus, the in-process whole blood pump PP1 can maintain acontinuous supply of blood to the blood separator, while the donorinterface pump PP3 is simultaneously used to draw and return blood tothe donor through the single phlebotomy needle. Processing time isthereby minimized.

In this arrangement, the universal pump station PP2 can serve,regardless of the particular blood processing procedure performed, as aplasma pump, to convey plasma from the blood separator. The ability todedicate separate pumping functions provides a continuous flow of bloodinto and out of the separator, as well as to and from the donor.

The circuit 46 can be programmed, depending upon the objectives of theparticular blood processing procedure, to retain all or some of theplasma for storage or fractionation purposes, or to return all or someof the plasma to the donor. The circuit 46 can be further programmed,depending upon the objectives of the particular blood processingprocedure, to retain all or some of the red blood cells for storage, orto return all or some of the red blood cells to the donor. The circuit46 can also be programmed, depending upon the objectives of theparticular blood processing procedure, to retain all or some of thebuffy coat for storage, or to return all or some of the buffy coat tothe donor.

In a preferred embodiment, the programmable fluid circuit 46 isimplemented by use of a fluid pressure actuated cassette 28 (see FIG.6). The cassette 28 provides a centralized, programmable, integratedplatform for all the pumping and valving functions required for a givenblood processing procedure. In the illustrated embodiment, the fluidpressure comprising positive and negative pneumatic pressure. Othertypes of fluid pressure can be used.

As FIG. 6 shows, the cassette 28 interacts with a pneumatic actuatedpump and valve station 30, which is mounted in the lid of the 40 of thecase 36 (see FIG. 1). The cassette 28 is, in use, mounted in the pumpand valve station 30. The pump and valve station 30 apply positive andnegative pneumatic pressure upon the cassette 28 to direct liquid flowthrough the circuit. Further details will be provided later.

The cassette 28 can take various forms. As illustrated (see FIG. 6), thecassette 28 comprises an injection molded body 188 having a front side190 and a back side 192. For the purposes of description, the front side190 is the side of the cassette 28 that, when the cassette 28 is mountedin the pump and valve station 30, faces away from the operator. Flexiblediaphragms 194 and 196 overlay both the front side 190 and back sides192 of the cassette 28, respectively.

The cassette body 188 is preferably made of a rigid medical gradeplastic material. The diaphragms 194 and 196 are preferably made offlexible sheets of medical grade plastic. The diaphragms 194 and 196 aresealed about their peripheries to the peripheral edges of the front andback sides of the cassette body 188. Interior regions of the diaphragms194 and 196 can also be sealed to interior regions of the cassette body188.

The cassette body 188 has an array of interior cavities formed on boththe front and back sides 190 and 192 (see FIGS. 7 and 9). The interiorcavities define the valve stations and flow paths shown schematically inFIG. 5. An additional interior cavity is provided in the back side ofthe cassette 28 to form a station that holds a filter material 200. Inthe illustrated embodiment, the filter material 200 comprises anovermolded mesh filter construction. The filter material 200 isintended, during use, to remove clots and cellular aggregations that canform during blood processing.

The pump stations PP1 to PP4 are formed as wells that are-open on thefront side 190 of the cassette body 188. Upstanding edges peripherallysurround the open wells of the pump stations. The pump wells are closedon the back side 192 of the cassette body 188, except for a spaced pairof through holes or ports 202 and 204 for each pump station. The ports202 and 204 extend through to the back side 192 of the cassette body188. As will become apparent, either port 202 or 204 can serve itsassociated pump station as an inlet or an outlet, or both inlet andoutlet.

The in line valves V1 to V23 are likewise formed as wells that are openon the front side 190 of the cassette. FIG. 8 shows a typical valveV(N). Upstanding edges peripherally surround the open wells of thevalves on the front side 190 of the cassette body 188. The valves areclosed on the back side 192 of the cassette 28, except that each valveincludes a pair of through holes or ports 206 and 208. One port 206communicates with a selected liquid path on the back side 192 of thecassette body 188. The other port 208 communicates with another selectedliquid path on the back side 192 of the cassette body 188.

In each valve, a valve seat 210 extends about one of the ports 208. Thevalve seat 210 is recessed below the surface of the recessed valve well,such that the port 208 is essentially flush with the surrounding surfaceof recessed valve well, and the valve seat 210 extends below than thesurface of the valve well.

The flexible diaphragm 194 overlying the front side 190 of the cassette28 rests against the upstanding peripheral edges surrounding the pumpstations and valves. With the application of positive force uniformlyagainst this side of the cassette body 188, the flexible diaphragm 194seats against the upstanding edges. The positive force forms peripheralseals about the pump stations and valves. This, in turn, isolates thepumps and valves from each other and the rest of the system. The pumpand valve station 30 applies positive force to the front side 190 of thecassette body 188 for this purpose.

Further localized application of positive and negative fluid pressuresupon the regions of the diaphragm 194 overlying these peripherallysealed areas serve to flex the diaphragm regions in these peripherallysealed areas. These localized applications of positive and negativefluid pressures on these diaphragm regions overlying the pump stationsserve to expel liquid out of the pump stations (with application ofpositive pressure) and draw liquid into the pump stations (withapplication of negative pressure).

In the illustrated embodiment, the bottom of each pump station PP1 toPP4 includes a recessed race 316 (see FIG. 7). The race 316 extendsbetween the ports 202 and 204, and also includes a dogleg extending atan angle from the top port 202. The race 316 provides better liquid flowcontinuity between the ports 202 and 204, particularly when thediaphragm region is forced by positive pressure against the bottom ofthe pump station. The race 316 also prevents the diaphragm region fromtrapping air within the pump station. Air within the pump station isforced into the race 316, where it can be readily venting through thetop port 202 out of the pump station, even if the diaphragm region isbottomed out in the station.

Likewise, localized applications of positive and negative fluid pressureon the diaphragm regions overlying the valves will serve to seat (withapplication of positive pressure) and unseat (with application ofnegative pressure) these diaphragm regions against the valve seats,thereby closing and opening the associated valve port. The flexiblediaphragm is responsive to an applied negative pressure for flexure outof the valve seat 210 to open the respective port. The flexiblediaphragm is responsive to an applied positive pressure for flexure intothe valve seat 210 to close the respective port. Sealing is accomplishedby forcing the flexible diaphragm to flex into the recessed valve seat210, to seal about the port 208, which is flush with wall of the valvewell. The flexible diaphragm forms within the recessed valve seat 210 aperipheral seal about the valve port 208.

In operation, the pump and valve station 30 applies localized positiveand negative fluid pressures to these regions of front diaphragm 104 foropening and closing the valve ports.

The liquid paths F1 to F38 are formed as elongated channels that areopen on the back side 192 of the cassette body 188, except for theliquid paths F15, F23, and F24 are formed as elongated channels that areopen on the front side 190 of the cassette body 188. The liquid pathsare shaded in FIG. 9 to facilitate their viewing. Upstanding edgesperipherally surround the open channels on the front and back sides 190and 192 of the cassette body 188.

The liquid paths F1 to F38 are closed on the front side 190 of thecassette body 188, except where the channels cross over valve stationports or pump station ports. Likewise, the liquid paths F31 to F38 areclosed on the back side 192 of the cassette body 188, except where thechannels cross over in-line ports communicating with certain channels onthe back side 192 of the cassette 28.

The flexible diaphragms 194 and 196 overlying the front and back sides190 and 192 of the cassette body 188 rest against the upstandingperipheral edges surrounding the liquid paths F1 to F38. With theapplication of positive force uniformly against the front and back sides190 and 192 of the cassette body 188, the flexible diaphragms 194 and196 seat against the upstanding edges. This forms peripheral seals alongthe liquid paths F1 to F38. In operation, the pump and valve station 30applies positive force to the diaphragms 194 and 196 for this purpose.

The pre-molded ports P1 to P13 extend out along two side edges of thecassette body 188. The cassette 28 is vertically mounted for use in thepump and valve station 30 (see FIG. 2). In this orientation, the portsP8 to P13 face downward, and the ports P1 to P7 are vertically stackedone above the other and face inward.

As FIG. 2 shows, the ports P8 to P13, by facing downward, are orientedwith container support trays 212 formed in the base 38, as will bedescribed later. The ports P1 to P7, facing inward, are oriented withthe centrifuge station 20 and a container weigh station 214, as willalso be described in greater detail later. The orientation of the portsP5 to P7 (which serve the processing chamber 18) below the ports P1 toP4 keeps air from entering the processing chamber 18.

This ordered orientation of the ports provides a centralized, compactunit aligned with the operative regions of the case 36.

B. The Universal Set

FIG. 10 schematically shows a universal set 264, which, by selectiveprogramming of the blood processing circuit 46 implemented by cassette28, is capable of performing several different blood processingprocedures.

The universal set 264 includes a donor tube 266, which is attached(through y-connectors 272 and 273) to tubing 300 having an attachedphlebotomy needle 268. The donor tube 266 is coupled to the port P8 ofthe cassette 28.

A container 275 for collecting an in-line sample of blood drawn throughthe tube 300 is also attached through the y-connector 273.

An anticoagulant tube 270 is coupled to the phlebotomy needle 268 viathe y-connector 272. The anticoagulant tube 270 is coupled to cassetteport P9. A container 276 holding anticoagulant is coupled via a tube 274to the cassette port P10. The anticoagulant tube 270 carries anexternal, manually operated in line clamp 282 of conventionalconstruction.

A container 280 holding a red blood cell additive solution is coupledvia a tube 278 to the cassette port P3. The tube 278 also carries anexternal, manually operated in line clamp 282.

A container 288 holding saline is coupled via a tube 284 to the cassetteport P12.

FIG. 10 shows the fluid holding containers 276, 280, and 288 as beingintegrally attached during manufacture of the set 264. Alternatively,all or some of the containers 276, 280, and 288 can be supplied separatefrom the set 264. The containers 276, 280, and 288 may be coupled byconventional spike connectors, or the set 264 may be configured toaccommodate the attachment of the separate container or containers atthe time of use through a suitable sterile connection, to therebymaintain a sterile, closed blood processing environment. Alternatively,the tubes 274, 278, and 284 can carry an in-line sterilizing filter anda conventional spike connector for insertion into a container port attime of use, to thereby maintain a sterile, closed blood processingenvironment.

The set 264 further includes tubes 290, 292, 294, which extend to anumbilicus 296. When installed in the processing station, the umbilicus296 links the rotating processing chamber 18 with the cassette 28without need for rotating seals. Further details of this constructionwill be provided later.

The tubes 290, 292, and 294 are coupled, respectively, to the cassetteports P5, P6, and P7. The tube 290 conveys whole blood into theprocessing chamber 18. The tube 292 conveys plasma from the processingchamber 18. The tube 294 conveys red blood cells from processing chamber18.

A plasma collection container 304 is coupled by a tube 302 to thecassette port P3. The collection container 304 is intended, in use, toserve as a reservoir for plasma during processing.

A red blood cell collection container 308 is coupled by a tube 306 tothe cassette port P2. The collection container 308 is intended, in use,to receive a first unit of red blood cells for storage.

A whole blood reservoir 312 is coupled by a tube 310 to the cassetteport P1. The collection container 312 is intended, in use, to serve as areservoir for whole blood during processing. It can also serve toreceive a second unit of red blood cells for storage.

As shown in FIG. 10, no tubing is coupled to the utility cassette portP13 and buffy port P4.

C. The Pump and Valve Station

The pump and valve station 30 includes a cassette holder 216. The door32 is hinged to move with respect to the cassette holder 216 between theopened position, exposing the cassette holder 216 (shown in FIG. 6) andthe closed position, covering the cassette holder 216 (shown in FIG. 3).The door 32 also includes an over center latch 218 with a latch handle220. When the door 32 is closed, the latch 218 swings into engagementwith the latch pin 222.

As FIG. 11 shows, the inside face of the door 32 carries an elastomericgasket 224. The gasket 224 contacts the back side 192 of the cassette 28when the door 32 is closed. An inflatable bladder 314 underlies thegasket 224. With the door 32 opened (see FIG. 2) the operator can placethe cassette 28 into the cassette holder 216. Closing the door 32 andsecuring the latch 218 brings the gasket 224 into facing contact withthe diaphragm 196 on the back side 192 of the cassette 28. Inflating thebladder 314 presses the gasket 224 into intimate, sealing engagementagainst the diaphragm 196. The cassette 28 is thereby secured in atight, sealing fit within the cassette holder 216.

The inflation of the bladder 314 also fully loads the over center latch218 against the latch pin 222 with a force that cannot be overcome bynormal manual force against the latch handle 220. The door 32 issecurely locked and cannot be opened when the bladder 314 is inflated.In this construction, there is no need for an auxiliary lock-out deviceor sensor to assure against opening of the door 32 during bloodprocessing.

The pump and valve station 30 also includes a manifold assembly 226located in the cassette holder 216. The manifold assembly 226 comprisesa molded or machined plastic or metal body. The front side 194 of thediaphragm is held in intimate engagement against the manifold assembly226 when the door 32 is closed and bladder 314 inflated.

The manifold assembly 226 is coupled to a pneumatic pressure source 234,which supplies positive and negative air pressure. The pneumaticpressure source 234 is carried inside the lid 40 behind the manifoldassembly 226.

In the illustrated embodiment, the pressure source 234 comprises twocompressors C1 and C2. However, one or several dual-head compressorscould be used as well. As FIG. 12 shows, one compressor C1 suppliesnegative pressure through the manifold 226 to the cassette 28. The othercompressor C2 supplies positive pressure through the manifold 226 to thecassette 28.

As FIG. 12 shows, the manifold 226 contains four pump actuators PA1 toPA4 and twenty-three valve actuators VA1 to VA23. The pump actuators PA1to PA4 and the valve actuators VA1 to VA23 are mutually oriented to forma mirror image of the pump stations PP1 to PP4 and valve stations V1 toV23 on the front side 190 of the cassette 28.

As FIG. 22 also shows, each actuator PA1 to PA4 and VA1 to VA23 includesa port 228. The ports 228 convey positive or negative pneumaticpressures from the source in a sequence governed by the controller 16.These positive and negative pressure pulses flex the front diaphragm 194to operate the pump chambers PP1 to PP4 and valve stations V1 to V23 inthe cassette 28. This, in turn, moves blood and processing liquidthrough the cassette 28.

The cassette holder 216 preferably includes an integral elastomericmembrane 232 (see FIG. 6) stretched across the manifold assembly 226.The membrane 232 serves as the interface between the piston element 226and the diaphragm 194 of the cassette 28, when fitted into the holder216. The membrane 232 may include one or more small through holes (notshown) in the regions overlying the pump and valve actuators PA1 to PA4and V1 to V23. The holes are sized to convey pneumatic fluid pressurefrom the manifold assembly 226 to the cassette diaphragm 194. Still, theholes are small enough to retard the passage of liquid. The membrane 232forms a flexible splash guard across the exposed face of the manifoldassembly 226.

The splash guard membrane 232 keeps liquid out of the pump and valveactuators PA1 to PA4 and VA1 to VA23, should the cassette diaphragm 194leak. The splash guard membrane 232 also serves as a filter to keepparticulate matter out of the pump and valve actuators of the manifoldassembly 226. The splash guard membrane 232 can be periodically wipedclean when cassettes 28 are exchanged.

The manifold assembly 226 includes an array of solenoid actuatedpneumatic valves, which are coupled inline with the pump and valveactuators PA1 to PA4 and VA1 to VA23. The manifold assembly 226, underthe control of the controller 16, selectively distributes the differentpressure and vacuum levels to the pump and valve actuators PA(N) andVA(N). These levels of pressure and vacuum are systematically applied tothe cassette 28, to route blood and processing liquids.

Under the control of a controller 16, the manifold assembly 226 alsodistributes pressure levels to the door bladder 314 (already described),as well as to a donor pressure cuff (not shown) and to a donor lineoccluder 320.

As FIG. 1 shows, the donor line occluder 320 is located in the case 36,immediately below the pump and valve station 30, in alignment with theports P8 and P9 of the cassette 28. The donor line 266, coupled to theport P8, passes through the occluder 320. The anticoagulant line 270,coupled to the port P9, also passes through the occluder 320. Theoccluder 320 is a spring loaded, normally closed pinch valve, betweenwhich the lines 266 and 270 pass. Pneumatic pressure from the manifoldassembly 234 is supplied to a bladder (not shown) through a solenoidvalve. The bladder, when expanded with pneumatic pressure, opens thepinch valve, to thereby open the lines 266 and 270. In the absence ofpneumatic pressure, the solenoid valve closes and the bladder vents toatmosphere. The spring loaded pinch valve of the occluder 320 closes,thereby closing the lines 266 and 270.

The manifold assembly 226 maintains several different pressure andvacuum conditions, under the control of the controller 16. In theillustrated embodiment, the following multiple pressure and vacuumconditions are maintained:

(i) Phard, or Hard Pressure, and Pinpr, or In-Process Pressure are thehighest pressures maintained in the manifold assembly 226. Phard isapplied for closing cassette valves V1 to V23. Pinpr is applied to drivethe expression of liquid from the in-process pump PP1 and the plasmapump PP2. A typical pressure level for Phard and Pinpr in the context ofthe preferred embodiment is 500 mmHg.

(ii) Pgen, or General Pressure, is applied to drive the expression ofliquid from the donor interface pump PP3 and the anticoagulant pump PP4.A typical pressure level for Pgen in the context of the preferredembodiment is 150 mmHg.

(iii) Pcuff, or Cuff Pressure, is supplied to the donor pressure cuff. Atypical pressure level for Pcuff in the context of the preferredembodiment is 80 mmHg.

(iv) Vhard, or Hard Vacuum, is the deepest vacuum applied in themanifold assembly 226. Vhard is applied to open cassette valves V1 toV23. A typical vacuum level for Vhard in the context of the preferredembodiment is −350 mmHg.

(vi) Vgen, or)General Vacuum, is applied to drive the draw function ofeach of the four pumps PP1 to PP4. A typical pressure level for Vgen inthe context of the preferred embodiment is −300 mmHg.

(vii) Pdoor, or Door Pressure, is applied to the bladder 314 to seal thecassette 28 into the holder 216. A typical pressure level for Pdoor inthe context of the preferred embodiment is 700 mmHg.

For each pressure and vacuum level, a variation of plus or minus 20 mmHgis tolerated.

Pinpr is used to operate the in process pump PP1, to pump blood into theprocessing chamber 18. The magnitude of Pinpr must be sufficient toovercome a minimum pressure of approximately 300 mm Hg, which istypically present within the processing chamber 18.

Similarly, Pinpr is used for the plasma pump PP2, since it must havesimilar pressure capabilities in the event that plasma needs to bepumped backwards into the processing chamber 18, e.g., during a spillcondition, as will be described later.

Pinpr and Phard are operated at the highest pressure to ensure thatupstream and downstream valves used in conjunction with pumping are notforced opened by the pressures applied to operate the pumps. Thecascaded, interconnectable design of the fluid paths F1 to F38 throughthe cassette 28 requires Pinpr-Phard to be the highest pressure applied.By the same token, Vgen is required to be less extreme than Vhard, toensure that pumps PP1 to PP4 do not overwhelm upstream and downstreamcassette valves V1 to V23.

Pgen is used to drive the donor interface pump PP3 and can be maintainedat a lower pressure, as can the AC pump PP4.

A main hard pressure line 322 and a main vacuum line 324 distributePhard and Vhard in the manifold assembly 324. The pressure and vacuumsources 234 run continuously to supply Phard to the hard pressure line322 and Vhard to the hard vacuum line 324.

A pressure sensor S1 monitors Phard in the hard pressure line 322. Thesensor S1 controls a solenoid 38. The solenoid 38 is normally closed.The sensor S1 opens the solenoid 38 to build Phard up to its maximum setvalue. Solenoid 38 is closed as long as Phard is within its specifiedpressure range and is opened when Phard falls below its minimumacceptable value.

Similarly, a pressure sensor S5 in the hard vacuum line 324 monitorsVhard. The sensor S5 controls a solenoid 39. The solenoid 39 is normallyclosed. The sensor S5 opens the solenoid 39 to build Vhard up to itsmaximum value. Solenoid 39 is closed as long as Vhard is within itsspecified pressure range and is opened when Vhard falls outside itsspecified range.

A general pressure line 326 branches from the hard pressure line 322. Asensor S2 in the general pressure line 326 monitors Pgen. The sensor 32controls a solenoid 30. The solenoid 30 is normally closed. The sensorS2 opens the solenoid 30 to refresh Pgen from the hard pressure line322, up to the maximum value of Pgen. Solenoid 30 is closed as long asPgen is within its specified pressure range and is opened when Pgenfalls outside its specified range.

An in process pressure line 328 also branches from the hard pressureline 322. A sensor S3 in the in process pressure line 328 monitorsPinpr. The sensor S3 controls a solenoid 36. The solenoid 36 is normallyclosed. The sensor S3 opens the solenoid 36 to refresh Pinpr from thehard pressure line 322, up to the maximum value of Pinpr. Solenoid 36 isclosed as long as Pinpr is within its specified pressure range and isopened when Pinpr falls outside its specified range.

A general vacuum line 330 branches from the hard vacuum line 324. Asensor S6 monitors Vgen in the general vacuum line 330. The sensor S6controls a solenoid 31. The solenoid 31 is normally closed. The sensorS6 opens the solenoid 31 to refresh Vgen from the hard vacuum line 324,up to the maximum value of Vgen. The solenoid 31 is closed as long asVgen is within its specified range and is opened when Vgen falls outsideits specified range.

In-line reservoirs R1 to R5 are provided in the hard pressure line 322,the in process pressure line 328, the general pressure line 326, thehard vacuum line 324, and the general vacuum line 330. The reservoirs R1to R5 assure that the constant pressure and vacuum adjustments as abovedescribed are smooth and predictable.

The solenoids 33 and 34 provide a vent for the pressures and vacuums,respectively, upon procedure completion. Since pumping and valving willcontinually consume pressure and vacuum, the solenoids 33 and 34 arenormally closed. The solenoids 33 and 34 are opened to vent the manifoldassembly upon the completion of a blood processing procedure.

The solenoids 28, 29, 35, 37 and 32 provide the capability to isolatethe reservoirs R1 to R5 from the air lines that supply vacuum andpressure to the manifold assembly 226. This provides for much quickerpressure/vacuum decay feedback, so that testing of cassette/manifoldassembly seal integrity can be accomplished. These solenoids 28, 29, 35,37, and 32 are normally opened, so that pressure cannot be built in theassembly 226 without a command to close the solenoids 28, 29, 35, 37,and 32, and, further, so that the system pressures and vacuums can ventin an error mode or with loss of power.

The solenoids 1 to 23 provide Phard or Vhard to drive the valveactuators VA1 to V23. In the unpowered state, these solenoids arenormally opened to keep all cassette valves V1 to V23 closed.

The solenoids 24 and 25 provide Pinpr and Vgen to drive the in-processand plasma pumps PP1 and PP2. In the unpowered state, these solenoidsare opened to keep both pumps PP1 and PP2 closed.

The solenoids 26 and 27 provide Pgen and Vgen to drive the donorinterface and AC pumps PP3 and PP4. In the unpowered state, thesesolenoids are opened to keep both pumps PP3 and PP4 closed.

The solenoid 43 provides isolation of the door bladder 314 from the hardpressure line 322 during the procedure. The solenoid 43 is normallyopened and is closed when Pdoor is reached. A sensor S7 monitors Pdoorand signals when the bladder pressure falls below Pdoor. The solenoid 43is opened in the unpowered state to ensure bladder 314 venting, as thecassette 28 cannot be removed from the holder while the door bladder 314is pressurized.

The solenoid 42 provides Phard to open the safety occluder valve 320.Any error modes that might endanger the donor will relax (vent) thesolenoid 42 to close the occluder 320 and isolate the donor. Similarly,any loss of power will relax the solenoid 42 and isolate the donor.

The sensor S4-monitors Pcuff and communicates with solenoids 41 (forincreases in pressure) and solenoid 40 (for venting) to maintain thedonor cuff within its specified ranges during the procedure. Thesolenoid 40 is normally open so that the cuff line will vent in theevent of system error or loss of power. The solenoid 41 is normallyclosed to isolate the donor from any Phard in the event of power loss orsystem error.

FIG. 12 shows a sensor S8 in the pneumatic line serving the donorinterface pump actuator PA3. The sensor S8 is a bi-directional mass airflow sensor, which can monitor air flow to the donor interface pumpactuator PA3 to detect occlusions in the donor line. Alternatively, aswill be described in greater detail later, electrical field variationscan be sensed by an electrode carried within the donor interface pumpchamber PP3, or any or all other pump chambers PP1, PP2, or PP4, todetect occlusions, as well as to permit calculation of flow rates andthe detection of air.

Various alternative embodiments are possible. For example, the pressureand vacuum available to the four pumping chambers could be modified toinclude more or less distinct levels or different groupings of “shared”pressure and vacuum levels. As another example, Vhard could be removedfrom access to the solenoids 2, 5, 8, 18, 19, 21, 22 since the restoringsprings will return the cassette valves to a closed position uponremoval of a vacuum. Furthermore, the vents shown as grouped togethercould be isolated or joined in numerous combinations.

It should also be appreciated that any of the solenoids used in“normally open” mode could be re-routed pneumatically to be realized as“normally closed”. Similarly, any of the “normally closed” solenoidscould be realized as “normally open”.

As another example of an alternative embodiment, the hard pressurereservoir R1 could be removed if Pdoor and Phard were set to identicalmagnitudes. In this arrangement, the door bladder 314 could serve as thehard pressure reservoir. The pressure sensor S7 and the solenoid 43would also be removed in this arrangement.

III. Other Process Control Components of the System

As FIG. 13 best shows, the case 36 contains other components compactlyarranged to aid blood processing. In addition to the centrifuge station20 and pump and valve station 30, already described, the case 36includes a weigh station 238, an operator interface station 240, and oneor more trays 212 or hangers 248 for containers. The arrangement ofthese components in the case 36 can vary. In the illustrated embodiment,the weigh station 238, the controller 16, and the user interface station240, like the pump and valve station 30, are located in the lid 40 ofthe case 36. The holding trays 212 are located in base 38 of the case36, adjacent the centrifuge station 20.

A. Container Support Components

The weigh station 238 comprises a series of container hangers/weighsensors 246 arranged along the top of the lid 40. In use (see FIG. 2),containers 304, 308, 312 are suspended on the hangers/weigh sensors 246.

The containers receive blood components separated during processing, aswill be described in greater detail later. The weigh sensors 246 provideoutput reflecting weight changes over time. This output is conveyed tothe controller 16. The controller 16 processes the incremental weightchanges to derive fluid processing volumes and flow rates. Thecontroller generates signals to control processing events based, inpart, upon the derived processing volumes. Further details of theoperation of the controller to control processing events will beprovided later.

The holding trays 212 comprise molded recesses in the base 38. The trays212 accommodate the containers 276 and 280 (see FIG. 2). In theillustrated embodiment, an additional swing-out hanger 248 is alsoprovided on the side of the lid 40. The hanger 248 (see FIG. 2) supportsthe container 288 during processing. In the illustrated embodiment, thetrays 212 and hanger 248 also include weigh sensors 246.

The weigh sensors 246 can be variously constructed. In the embodimentshown in FIG. 40, the scale includes a force sensor 404 incorporatedinto a housing 400, to which a hanger 402 is attached. The top surface420 of hanger 402 engages a spring 406 on the sensor 404. Another spring418 is compressed as a load, carried by the hanger 402, is applied. Thespring 418 resists load movement of the hanger 402, until the loadexceeds a predetermined weight (e.g., 2 kg.). At that time, the hanger402 bottoms out on mechanical stops 408 in the housing 400, therebyproviding over load protection.

In the embodiment shown in FIG. 41, a supported beam 410 transfers forceapplied by a hanger 416 to a force sensor 412 through a spring 414. Thisdesign virtually eliminates friction from the weight sensing system. Themagnitude of the load carried by the beam is linear in behavior, and theweight sensing system can be readily calibrated to ascertain an actualload applied to the hanger 416.

B. The Controller and Operator Interface Station

The controller 16 carries out process control and monitoring functionsfor the system 10. As FIG. 14 shows schematically, the controller 16comprises a main processing unit (MPU) 250, which can comprise, e.g., aPentium™ type microprocessor made by Intel Corporation, although othertypes of conventional microprocessors can be used. The MPU 250 ismounted inside the lid 40 of the case 36 (as FIG. 13 shows).

In the preferred embodiment, the MPU 250 employs conventional real timemulti-tasking to allocate MPU cycles to processing tasks. A periodictimer interrupt (for example, every 5 milliseconds) preempts theexecuting task and schedules another that is in a ready state forexecution. If a reschedule is requested, the highest priority task inthe ready state is scheduled. Otherwise, the next task on the list inthe ready state is scheduled.

As FIG. 14 shows, the MPU 250 includes an application control manager252. The application control manager 252 administers the activation of alibrary of at least one control application 254. Each controlapplication 254 prescribes procedures for carrying out given functionaltasks using the centrifuge station 20 and the pump and valve station 30in a predetermined way. In the illustrated embodiment, the applications254 reside as process software in EPROM's in the MPU 250.

The number of applications 254 can vary. In the illustrated embodiment,the applications 254 includes at least one clinical procedureapplication. The procedure application contains the steps to carry outone prescribed clinical processing procedure. For the sake of example inthe illustrated embodiment, the application 254 includes three procedureapplications: (1) a double unit red blood cell collection procedure; (2)a plasma collection procedure; and (3) a plasma/red blood cellcollection procedure. The details of these procedures will be describedlater. Of course, additional procedure applications can be included.

As FIG. 14 shows, several slave processing units communicate with theapplication control manager 252. While the number of slave processingunits can vary, the illustrated embodiment shows five units 256(1) to256 (5). The slave processing units 256 (1) to 256 (5), in turn,communicates with low level peripheral controllers 258 for controllingthe pneumatic pressures within the manifold assembly 226, the weighsensors 246, the pump and valve actuators PA1 to PA4 and VA1 to VA23 inthe pump and valve station 30, the motor for the centrifuge station 20,the interface sensing station 332, and other functional hardware of thesystem.

The MPU 250 contains in EPROM's the commands for the peripheralcontrollers 258, which are downloaded to the appropriate slaveprocessing unit 256(1) to 256(5) at start-up. The application controlmanager 252 also downloads to the appropriate slave processing unit 256(1) to 256(5) the operating parameters prescribed by the activatedapplication 254.

With this downloaded information, the slave processing units 256(1) to256(5) proceed to generate device commands for the peripheralcontrollers 258, causing the hardware to operate in a specified way tocarry out the procedure. The peripheral controllers 258 return currenthardware status information to the appropriate slave processing unit256(1) to 256(5), which, in turn, generate the commands necessary tomaintain the operating parameters ordered by the application controlmanager 252.

In the illustrated embodiment, one slave processing unit 256(2) performsthe function of an environmental manager. The unit 256(2) receivesredundant current hardware status information and reports to the MPU 250should a slave unit malfunction and fail to maintain the desiredoperating conditions.

As FIG. 14 shows, the MPU 250 also includes an interactive userinterface 260, which allows the operator to view and comprehendinformation regarding the operation of the system 10. The interface 260is coupled to the interface station 240. The interface 260 allows theoperator to use the interface station 240 to select applications 254residing in the application control manager 252, as well as to changecertain functions and performance criteria of the system 10.

As FIG. 13 shows, the interface station 240 includes an interface screen262 carried in the lid 40. The interface screen 262 displays informationfor viewing by the operator in alpha-numeric format and as graphicalimages. In the illustrated and preferred embodiment, the interfacescreen 262 also serves as an input device. It receives input from theoperator by conventional touch activation.

C. On-Line Monitoring of Pump Flows

1. Gravimetric Monitoring

Using the weigh scales 246, either upstream or downstream of the pumps,the controller 16 can continuously determine the actual volume of fluidthat is moved per pump stroke and correct for any deviations fromcommanded flow. The controller 16 can also diagnose exceptionalsituations, such as leaks and obstructions in the fluid path. Thismeasure of monitoring and control is desirable in an automated apheresisapplication, where anticoagulant has to be accurately metered with thewhole blood as it is drawn from the donor, and where product quality(e.g., hematocrit, plasma purity) is influenced by the accuracy of thepump flow rates.

The pumps PP1 to PP4 in the cassette 28 each provides arelatively-constant nominal stroke volume, or SV. The flow rate for agiven pump can therefore be expressed as follows:

$\begin{matrix}{Q = \frac{SV}{\left( {T_{Pump} + T_{Fill} + T_{Idle}} \right)}} & (1)\end{matrix}$

where:

Q is the flow rate of the pump.

SV is the stroke volume, or volume moved per pump cycle.

T_(Pump) is the time the fluid is moved out of the pump chamber.

T_(Fill) is the time the pump is filled with fluid, and

T_(Idle) is the time when the pump is idle, that is, when no fluidmovement occurs.

The SV can be affected by the interaction of the pump with attacheddownstream and upstream fluid circuits. This is analogous, in electricalcircuit theory, to the interaction of a non-ideal current source withthe input impedance of the load it sees. Because of this, the actual SVcan be different than the nominal SV.

The actual fluid flow in volume per unit of time Q_(Actual) cantherefore be expressed as follows:

$\begin{matrix}{Q_{Actual} = {k \times \frac{{SV}_{Ideal}}{T_{Pump} + T_{Fill} + T_{Idle}}}} & (2)\end{matrix}$

where:

Q_(Actual) is the actual fluid flow in volume per unit of time.

SV_(Ideal) is the theoretical stroke volume, based upon the geometry ofthe pump chamber.

k is a correction factor that accounts for the interactions between thepump and the upstream and downstream pressures.

The actual flow rate can be ascertained gravimetrically, using theupstream or downstream weigh scales 246, based upon the followingrelationship:

$\begin{matrix}{Q_{Actual} = \frac{\Delta\;{Wt}}{\rho \times \Delta\; T}} & (3)\end{matrix}$

where:

ΔWt is the change in weight of fluid as detected by the upstream ordownstream weigh scale 246 during the time period ΔT,

ρ is the density of fluid.

ΔT is the time period where the change in weight ΔWt is detected in theweigh scale 246.

The following expression is derived by combining Equations (2) and (3):

$\begin{matrix}{k = {\left( {T_{Pump} + T_{Fill} + T_{Idle}} \right) \times \frac{\Delta\;{Wt}}{\left( {{SV}_{Ideal} \times \rho \times \Delta\; T} \right)}}} & (4)\end{matrix}$

The controller 16 computes k according to Equation (4) and then adjustsT_(Idle) so that the desired flow rate is achieved, as follows:

$\begin{matrix}{T_{Idle} = {\left( {k \times \frac{{SV}_{Ideal}}{Q_{Desired}}} \right) - T_{Pump} - T_{Fill}}} & (5)\end{matrix}$

The controller 16 updates the values for k and T_(Idle) frequently toadjust the flow rates.

Alternatively, the controller 16 can change T_(pump) and/or T_(Fill)and/or T_(Idle) to adjust the flow rates.

In this arrangement, one or more of the time interval componentsT_(Pump), or T_(Fill), or T_(Idle) is adjusted to a new magnitude toachieve Q_(Desired), according to the following relationship:

$T_{n{({Adjusted})}} = {{k\left( \frac{{SV}_{Ideal}}{Q_{Desired}} \right)} - T_{n{({NotAdjusted})}}}$where:

T_(n(Adjusted)) is the magnitude of the time interval component orcomponents after adjustment to achieve the desired flow rateQ_(Desired).

T_(n(NotAdjusted)) is the magnitude of the value of the other timeinterval component or components of T_(stroke) that are not adjusted.The adjusted stroke interval after adjustment to achieve the desiredflow rate Q_(Desired) is the sum of T_(n(Adjusted)) andT_(n(NotAdjusted)).

The controller 16 also applies the correction factor k as a diagnosticstool to determine abnormal operating conditions. For example, if kdiffers significantly from its nominal value, the fluid path may haveeither a leak or an obstruction. Similarly, if computed value of k is ofa polarity different from what was expected, then the direction of thepump may be reversed.

With the weigh scales 246, the controller 16 can perform on-linediagnostics even if the pumps are not moving fluid. For example, if theweigh scales 246 detect changes in weight when no flow is expected, thena leaky valve or a leak in the set 264 may be present.

In computing k and T_(idle) and/or T_(pump) and/or T_(Fill), thecontroller 16 may rely upon multiple measurements of ΔWt and/or ΔT. Avariety of averaging or recursive techniques (e.g., recursive leastmeans squares, Kalman filtering, etc.) may be used to decrease the errorassociated with the estimation schemes.

The above described monitoring technique is applicable for use for otherconstant stroke volume pumps, i.e. peristaltic pumps, etc.

2. Electrical Monitoring

In an alternative arrangement (see FIG. 42), the controller 16 includesa metal electrode 422 located in the chamber of each pump station PP1 toPP4 on the cassette 28. The electrodes 422 are coupled to a currentsource 424. The passage of current through each electrode 422 creates anelectrical field within the respective pump chamber PP1 to PP4.

Cyclic deflection of the diaphragm 194 to draw fluid into and expelfluid from the pump chamber PP1 to PP4 changes the electrical field,resulting in a change in total capacitance of the circuit through theelectrode 422. Capacitance increases as fluid is draw into the pumpchamber PP1 to PP4, and capacitance decreases as fluid is expelled frompump chamber PP1 to PP4.

The controller 16 includes a capacitive sensor 426 (e.g., a QproxE2S)coupled to each electrode 422. The capacitive sensor 426 registerschanges in capacitance for the electrode 422 in each pump chamber PP1 toPP4. The capacitance signal for a given electrode 422 has a high signalmagnitude when the pump chamber is filled with liquid (diaphragmposition 194 a), has a low signal magnitude signal when the pump chamberis empty of fluid (diaphragm position 194 b), and has a range ofintermediate signal magnitudes when the diaphragm occupies positionsbetween position 194 a and 194 b.

At the outset of a blood processing procedure, the controller 16calibrates the difference between the high and low signal magnitudes foreach sensor to the maximum stroke volume SV of the respective pumpchamber. The controller 16 then relates the difference between sensedmaximum and minimum signal values during subsequent draw and expelcycles to fluid volume drawn and expelled through the pump chamber. Thecontroller 16 sums the fluid volumes pumped over a sample time period toyield an actual flow rate.

The controller 16 compares the actual flow rate to a desired flow rate.If a deviance exists, the controller 16 varies pneumatic pressure pulsesdelivered to the actuator PA1 to PA4, to adjust T_(Idle) and/or T_(Pump)and/or T_(Fill) to minimize the deviance.

The controller 16 also operates to detect abnormal operating conditionsbased upon the variations in the electric field and to generate an alarmoutput. In the illustrated embodiment, the controller 16 monitors for anincrease in the magnitude of the low signal magnitude over time. Theincrease in magnitude reflects the presence of air inside a pumpchamber.

In the illustrated embodiment, the controller 16 also generates aderivative of the signal output of the sensor 426. Changes in thederivative, or the absence of a derivative, reflects a partial orcomplete occlusion of flow through the pump chamber PP1 to PP4. Thederivative itself also varies in a distinct fashion depending uponwhether the occlusion occurs at the inlet or outlet of the pump chamberPP1 to PP4.

IV. The Blood Processing Procedures

A. Double RBC Collection Procedure (No Plasma Collection)

During this procedure, whole blood from a donor is centrifugallyprocessed to yield up to two units (approximately 500 ml) of red bloodcells for collection. All plasma constituent is returned to the donor.This procedure will, in shorthand, be called the double red blood cellcollection procedure.

Prior to undertaking the double red blood cell collection procedure, aswell as any blood collection procedure, the controller 16 operates themanifold assembly 226 to conduct an appropriate integrity check of thecassette 28, to determine whether there are any leaks in the cassette28. Once the cassette integrity check is complete and no leaks arefound, the controller 16 begins the desired blood collection procedure.

The double red blood cell collection procedure includes a pre-collectioncycle, a collection cycle, a post-collection cycle, and a storagepreparation cycle. During the pre-collection cycle, the set 264 isprimed to vent air prior to venipuncture. During the collection cycle,whole blood drawn from the donor is processed to collect two units ofred blood cells, while returning plasma to the donor. During thepost-collection cycle, excess plasma is returned to the donor, and theset is flushed with saline. During the storage preparation cycle, a redblood cell storage solution is added.

1. The Pre-Collection Cycle

a. Anticoagulant Prime

In a first phase of the pre-collection cycle (AC Prime 1), tube 300leading to the phlebotomy needle 268 is clamped closed (see FIG. 10).The blood processing circuit 46 is programmed (through the selectiveapplication of pressure to the valves and pump stations of the cassette)to operate the donor interface pump PP3, drawing anticoagulant throughthe anticoagulant tube 270 and up the donor tube 266 through they-connector 272 (i.e., in through valve V13 and out through valve V11).The circuit is further programmed to convey air residing in theanticoagulant tube 270, the donor tube 266, and the cassette and intothe in-process container 312. This phase continues until an air detector298 along the donor tube 266 detects liquid, confirming the pumpingfunction of the donor interface pump PP3.

In a second phase of the pre-collection cycle (AC Prime 2), the circuitis programmed to operate the anticoagulant pump PP4 to conveyanticoagulant into the in-process container 312. Weight changes in thein-process container 312. AC Prime 2 is terminated when theanticoagulant pump PP4 conveys a predetermined volume of anticoagulant(e.g., 10 g) into the in-process container 312, confirming is pumpingfunction.

b. Saline Prime

In a third phase of the pre-collection cycle (Saline Prime 1), theprocessing chamber 46 remains stationary. The circuit is programmed tooperate the in-process pump station PP1 to draw saline from the salinecontainer 288 through the in-process pump PP1. This creates a reverseflow of saline through the stationary processing chamber 46 toward thein-process container 312. In this sequence saline is drawn through theprocessing chamber 46 from the saline container 288 into the in-processpump PP1 through valve V14. The saline is expelled from the pump stationPP1 toward the in-process container 312 through valve 9. Weight changesin the saline container 288 are monitored. This phase is terminated uponregistering a predetermined weight change in the saline container 288,which indicates conveyance of a saline volume sufficient to initiallyfill about one half of the processing chamber 46 (e.g., about 60 g).

With the processing chamber 46 about half full of priming saline, afourth phase of the pre-collection cycle (Saline Prime 2). Theprocessing chamber 46 is rotated at a low rate (e.g., about 300 RPM),while the circuit continues to operate in the same fashion as in SalinePrime 3. Additional saline is drawn into the pump station PP1 throughvalve V14 and expelled out of the pump station PP1 through valve V9 andinto the in-process container 312. Weight changes in the in-processcontainer 312 are monitored. This phase is terminated upon registering apredetermined weight change in the in-process container 312, whichindicates the conveyance of an additional volume of saline sufficient tosubstantially fill the processing chamber 46 (e.g., about 80 g)

In a fifth phase of the pre-collection cycle (Saline Prime 3), thecircuit is programmed to first operate the in-process pump station PP1to convey saline from the in-process container 312 through all outletports of the separation device and back into the saline container 288through the plasma pump station PP2. This completes the priming of theprocessing chamber 46 and the in-process pump station PP1 (pumping inthrough valve V9 and out through valve V14), as well as primes theplasma pump station PP2, with the valves V7, V6, V10, and V12 opened toallow passive flow of saline. During this time, the rate at which theprocessing chamber 46 is rotated is successively ramped between zero and300 RPM. Weight changes in the in process container 312 are monitored.When a predetermined initial volume of saline is conveyed in thismanner, the circuit is programmed to close valve V7, open valves V9 andV14, and to commence pumping saline to the saline container 288 throughthe plasma pump PP2, in through valve V12 and out through valve V10,allowing saline to passively flow through the in-process pump PP1.Saline in returned in this manner from the in-process container 312 tothe saline container 288 until weight sensing indicated that apreestablished minimum volume of saline occupies the in-processcontainer 312.

In a sixth phase of the pre-collection cycle (Vent Donor Line), thecircuit is programmed to purge air from the venepuncture needle, priorto venipuncture, by operating the donor interface pump PP3 to pumpanticoagulant through anticoagulant pump PP4 and into the in processcontainer 312.

In a seventh phase of the pre-collection cycle (Venipuncture), thecircuit is programmed to close all valves V1 to V23, so thatvenipuncture can be accomplished.

The programming of the circuit during the phases of the pre-collectioncycle is summarized in the following table.

TABLE Programming of Blood Processing Circuit During Pre- CollectionCycle (Double Red Blood Cell Collection Procedure) Vent AC AC SalineSaline Saline Donor Veni- Phase Prime 1 Prime 2 Prime 1 Prime 2 Prime 3Line puncture V1 • • • • • • • V2 • • • • • • • V3 ∘ ∘ • • • ∘ • V4 • •∘ • • • • V5 • • • • • • • V6 • • • • ∘ • • V7 • • • • ∘ • • V8 • • • •• • • V9 • • ∘/• ∘/• ∘/• • • Pump Pump Pump In Out Out (Stage 1) ∘(Stage 2) V10 • • • • ∘ • • (Stage 1) ∘/• Pump Out (Stage 2) V11 ∘/• ∘ •• • ∘/• • Pump Pump In Out V12 • • • • ∘ • • (Stage 1) ∘/• Pump In(Stage 2) V13 ∘/• ∘ • • • ∘/• • Pump In Pump Out V14 • • ∘/• ∘/• ∘/• • •Pump In Pump In Pump Out (Stage 1) ∘ (Stage 2) V15 ∘ ∘/• • • • ∘ • PumpIn Pump Out V16 • • • • • • • V17 • • • • • • • V18 ∘ ∘ • • • ∘ • V19 ∘∘ • • • ∘ • V20 ∘ ∘/• • • • ∘ • Pump Out Pump In V21 • • • • • • • V22 •• ∘ ∘ ∘ • • V23 • • ∘ ∘ ∘ • • PP1 ▪ ▪ □ □ □ ▪ ▪ (Stage 1) PP2 ▪ ▪ ▪ ▪ □▪ ▪ (Stage 2) PP3 □ ▪ ▪ ▪ ▪ □ ▪ PP4 ▪ □ ▪ ▪ ▪ ▪ ▪ Caption: ∘ denotes anopen valve; • denotes a closed valve; ∘/• denotes a valve opening andclosing during a pumping sequence; ▪ denotes an idle pump station (notin use); and □ denotes a pump station in use.

c. The Collection Cycle

i. Blood Prime

With venipuncture, tube 300 leading to the phlebotomy needle 268 isopened. In a first phase of the collection cycle (Blood Prime 1), theblood processing circuit 46 is programmed (through the selectiveapplication of pressure to the valves and pump stations of the cassette)to operate the donor interface pump PP3 (i.e., in through valve V13 andout through valve V11) and the anticoagulant pump PP4 (i.e., in throughvalve V20 and out through valve V15) to draw anticoagulated bloodthrough the donor tube 270 into the in process container 312. This phasecontinues until an incremental volume of anticoagulated whole bloodenters the in process container 312, as monitored by the weigh sensor.

In a next phase (Blood Prime 2), the blood processing circuit 46 isprogrammed to operate the in-process pump station PP1 to drawanticoagulated blood from the in-process container 312 through theseparation device. During this phase, saline displaced by the blood isreturned to the donor. This phase primes the separation device withanticoagulated whole blood. This phase continues until an incrementalvolume of anticoagulated whole blood leaves the in process container312, as monitored by the weigh sensor.

B. Blood Separation While Drawing Whole Blood or Without Drawing WholeBlood

In a next phase of the blood collection cycle (Blood Separation WhileDrawing Whole Blood), the blood processing circuit 46 is programmed tooperate the donor interface pump station PP3 (i.e., in through valve V13and out through valve V11); the anticoagulant pump PP4 (i.e., in throughvalve V20 and out through valve V15); the in-process pump PP1 (i.e., inthrough valve V9 and out through valve V14); and the plasma pump PP2(i.e., in through valve V12 and out through valve V10). This arrangementdraws anticoagulated blood into the in-process container 312, whileconveying the blood from the in-process container 312 into theprocessing chamber for separation. This arrangement also removes plasmafrom the processing chamber into the plasma container 304, whileremoving red blood cells from the processing chamber into the red bloodcell container 308. This phase continues until an incremental volume ofplasma is collected in the plasma collection container 304 (as monitoredby the weigh sensor) or until a targeted volume of red blood cells iscollected in the red blood cell collection container (as monitored bythe weigh sensor).

If the volume of whole blood in the in-process container 312 reaches apredetermined maximum threshold before the targeted volume of eitherplasma or red blood cells is collected, the circuit is programmed foranother phase (Blood Separation Without Drawing Whole Blood), toterminate operation of the donor interface pump station PP3 (while alsoclosing valves V13, V11, V18, and V13) to terminate collection of wholeblood in the in-process container 312, while still continuing bloodseparation. If the volume of whole blood reaches a predetermined minimumthreshold in the in-process container 312 during blood separation, butbefore the targeted volume of either plasma or red blood cells iscollected, the circuit is programmed to return to the Blood SeparationWhile Drawing Whole Blood Phase, to thereby allow whole blood to enterthe in-process container 312. The circuit is programmed to togglebetween the Blood Separation While Drawing Whole Blood Phase and theBlood Separation Without Drawing Whole Blood Phase according to the highand low volume thresholds for the in-process container 312, until therequisite volume of plasma has been collected, or until the targetvolume of red blood cells has been collected, whichever occurs first.

C. Return Plasma and Saline

If the targeted volume of red blood cells has not been collected, thenext phase of the blood collection cycle (Return Plasma With Separation)programs the blood processing circuit 46 to operate the donor interfacepump station PP3 (i.e., in through valve V11 and out through valve V13);the in-process pump PP1 (i.e., in through valve V9 and out through valveV14); and the plasma pump PP2 (i.e., in through valve V12 and outthrough valve V10). This arrangement conveys anticoagulated whole bloodfrom the in-process container 312 into the processing chamber forseparation, while removing plasma into the plasma container 304 and redblood cells into the red blood cell container 308. This arrangement alsoconveys plasma from the plasma container 304 to the donor, while alsomixing saline from the container 288 in line with the returned plasma.The in line mixing of saline with plasma raises the saline temperatureand improves donor comfort. This phase continues until the plasmacontainer 304 is empty, as monitored by the weigh sensor.

If the volume of whole blood in the in-process container 312 reaches aspecified low threshold before the plasma container 304 empties, thecircuit is programmed to enter another phase (Return Plasma WithoutSeparation), to terminate operation of the in-process pump station PP1(while also closing valves V9, V10, V12, and V14) to terminate bloodseparation. The phase continues until the plasma container 304 empties.

Upon emptying the plasma container 304, the circuit is programmed toenter a phase (Fill Donor Line), to operate the donor interface pumpstation PP3 (i.e., in through valve V11 and out through valve V13) todraw whole blood from the in process container 312 to fill the donortube 266, thereby purge plasma (mixed with saline) in preparation foranother draw whole blood cycle.

The circuit is then programmed to conduct another Blood Separation WhileDrawing Whole Blood Phase, to refill the in process container 312. Thecircuit is programmed in successive Blood Separation and Return PlasmaPhases until the weigh sensor indicates that a desired volume of redblood cells have been collected in the red blood cell collectioncontainer 308. When the targeted volume of red blood cells has not beencollected, the post-collection cycle commences.

The programming of the circuit during the phases of the collection cycleis summarized in the following table.

TABLE Programming of Blood Processing Circuit During The CollectionCycle (Double Red Blood Cell Collection Procedure) Blood SeparationWhile Drawing Return Whole Blood Plasma/with (Without Separation Drawing(Without Fill Phase Blood Prime 1 Blood Prime 2 Whole Blood) Separation)Donor Line V1 • • • • ∘ V2 • • ∘ ∘ (•) • V3 ∘ • ∘ • • (•) V4 • • • • •V5 • • ∘ ∘ • V6 • • • ∘/• • Alternates with V23 V7 • ∘ • • ∘ V8 • • • •• V9 • ∘/• ∘/• ∘/• • Pump In Pump In Pump In (•) V10 • • ∘/• ∘/• • PumpOut Pump Out (•) V11 ∘/• ∘ ∘/• ∘/• ∘/• Pump Out Pump Out Pump In Pump In(•) V12 • • ∘/• ∘/• • Pump In Pump In (•) V13 ∘/• ∘ ∘/• ∘/• ∘/• Pump InPump In Pump Out Pump Out (•) V14 • ∘/• ∘/• ∘/• • Pump Out Pump Out PumpOut (•) V15 ∘/• • ∘/• • • Pump Out Pump Out (•) V16 • • • • • V17 • • •• • V18 ∘ ∘ ∘ ∘ ∘ (•) V19 ∘ • ∘ • • (•) V20 ∘/• • ∘/• • • Pump Out PumpIn (•) V21 • • • • • V22 • • • ∘ • V23 • • • ∘/• • Alternates with V6PP1 ▪ □ □ □ ▪ (▪) PP2 ▪ ▪ □ □ ▪ (▪) PP3 □ ▪ □ □ □ (▪) PP4 □ ▪ □ ▪ ▪ (▪)Caption: ∘ denotes an open valve; • denotes a closed valve; ∘/• denotesa valve opening and closing during a pumping sequence; ▪ denotes an idlepump station (not in use); and □ denotes a pump station in use.

D. The Post-Collection Cycle

Once the targeted volume of red blood cells has been collected (asmonitored by the weigh sensor), the circuit is programmed to carry outthe phases of the post-collection cycle.

1. Return Excess Plasma

In a first phase of the post-collection cycle (Excess Plasma Return),the circuit is programmed to terminate the supply and removal of bloodto and from the processing chamber, while operating the donor interfacepump station PP3 (i.e., in through valve V11 and out through valve V13)to convey plasma remaining in the plasma container 304 to the donor. Thecircuit is also programmed in this phase to mix saline from thecontainer 288 in line with the returned plasma. This phase continuesuntil the plasma container 304 is empty, as monitored by the weighsensor.

2. Saline Purge

In the next phase of the post-collection cycle (Saline Purge), thecircuit is programmed to operate the donor interface pump station PP3(i.e., in through valve V11 and out through valve V11) to convey salinefrom the container 288 through the separation device, to displace theblood contents of the separation device into the in-process container312, in preparation for their return to the donor. This phase reducesthe loss of donor blood. This phase continues until a predeterminedvolume of saline is pumped through the separation device, as monitoredby the weigh sensor.

3. Final Return to Donor

In the next phase of the post-collection cycle (Final Return), thecircuit is programmed to operate the donor interface pump station PP3(i.e., in through valve V11 and out through valve V13) to convey theblood contents of the in-process container 312 to the donor. Saline isintermittently mixed with the blood contents. This phase continues untilthe in-process container 312 is empty, as monitored by the weigh sensor.

In the next phase (Fluid Replacement), the circuit is programmed tooperate the donor interface pump station PP3 (i.e., in through valve V11and out through valve V13) to convey the saline to the donor. This phasecontinues until a prescribed replacement volume amount is infused, asmonitored by the weigh sensor.

In the next phase of the post-collection cycle (Empty In ProcessContainer), the circuit is programmed to operate the donor interfacepump station PP3 (i.e., in through valve V11 and out through valve V13)to convey all remaining contents of the in-process container 312 to thedonor, in preparation of splitting the contents of the red blood cellcontainer 308 for storage in both containers 308 and 312. This phasecontinues until a zero volume reading for the in-process container 312occurs, as monitored by the weigh sensor, and air is detected at the airdetector.

At this phase, the circuit is programmed to close all valves and idleall pump stations, so that the phlebotomy needle 268 can be removed fromthe donor.

The programming of the circuit during the phases of the post-collectioncycle is summarized in the following table.

Table Programming of Blood Processing Circuit During The Post-CollectionCycle (Double Red Blood Cell Collection Procedure)

Excess Empty In Plasma Saline Final Fluid Process Phase Return PurgeReturn Replacement Container V1 • • ∘ • ∘ V2 • • • • • V3 • • • • • V4 •∘ • • • V5 ∘ • • • • V6 ∘/• • • • • Alternates with V23 V7 • • ∘/• • ∘Alternates with V23 V8 • • • • • V9 ∘ ∘ • • • V10 • • • • • V11 ∘/• ∘/•∘/• ∘/• ∘/• Pump In Pump In/ Pump In Pump In Pump In Pump Out V12 • • •• • V13 ∘/• • ∘/• ∘/• ∘/• Pump Out Pump Out Pump Out Pump Out V14 • ∘ •• • V15 • • • • • V16 • • • • • V17 • • • • • V18 ∘ • ∘ ∘ ∘ V19 • • • •• V20 • • • • • V21 • • • • • V22 ∘ ∘ ∘ ∘ • V23 ∘/• ∘ ∘/• ∘ • AlternatesAlternates with V6 with V7 PP1 ▪ ▪ ▪ ▪ ▪ PP2 ▪ ▪ ▪ ▪ ▪ PP3 □ □ □ □ □ PP4▪ ▪ ▪ ▪ ▪ Caption: ∘ denotes an open valve; • denotes a closed valve;∘/• denotes a valve opening and closing during a pumping sequence; ▪denotes an idle pump station (not in use); and □ denotes a pump stationin use.

E. The Storage Preparation Cycle

1. Split RBC

In the first phase of the storage preparation cycle (Split RBC), thecircuit is programmed to operate the donor interface pump station PP3 totransfer half of the contents of the red blood cell collection container308 into the in-process container 312. The volume pumped is monitored bythe weigh sensors for the containers 308 and 312.

2. Add RBC Preservative

In the next phases of the storage preparation cycle (Add StorageSolution to the In Process Container and Add Storage Solution to the RedBlood Cell Collection Container), the circuit is programmed to operatethe donor interface pump station PP3 to transfer a desired volume of redblood cell storage solution from the container 280 first into thein-process container 312 and then into the red blood cell collectioncontainer 308. The transfer of the desired volume is monitored by theweigh scale.

In the next and final phase (End Procedure), the circuit is programmedto close all valves and idle all pump stations, so that the red bloodcell containers 308 and 312 can be separated and removed for storage.The remainder of the disposable set can now be removed and discarded.

The programming of the circuit during the phases of the storagepreparation cycle is summarized in the following table.

TABLE Programming of Blood Processing Circuit During The StoragePreparation Cycle (Double Red Blood Cell Collection Procedure) Split RBCBetween RBC Add Storage Collection Add Storage Solution to End and InSolution to In RBC Procedure Process Process Collection (Remove PhaseContainers Container Container Venipuncture) V1 • • • • V2 ∘ • ∘ • V3∘/• ∘ • • Alternates with V11 and V4 V4 ∘/• • ∘ • Alternates with V11and V4 V5 • • • • V6 • • • • V7 • • • • V8 • • • • V9 • • • • V10 • • •• V11 ∘/• ∘/• ∘/• • Pump In/ Pump In/ Pump In/ Pump Out Pump Out PumpOut V12 • • • • V13 • • • • V14 • • • • V15 • • • • V16 • ∘ ∘ • V17 • •• • V18 • • • • V19 • • • • V20 • • • • V21 • ∘ ∘ • V22 • • • • V23 • •• • PP1 ▪ ▪ ▪ ▪ PP2 ▪ ▪ ▪ ▪ PP3 □ □ □ ▪ PP4 ▪ ▪ ▪ ▪ Caption: ∘ denotesan open valve; • denotes a closed valve; ∘/• denotes a valve opening andclosing during a pumping sequence; ▪ denotes an idle pump station (notin use); and □ denotes a pump station in use.

F. Plasma Collection (No Red Blood Cell Collection)

During this procedure, whole blood from a donor is centrifugallyprocessed to yield up to 880 ml of plasma for collection. All red bloodcells are returned to the donor. This procedure will, in shorthand, becalled the plasma collection procedure.

Programming of the blood processing circuit 46 (through the selectiveapplication of pressure to the valves and pump stations of the cassette)makes it possible to use the same universal set 264 as in the double redblood cell collection procedure.

The procedure includes a pre-collection cycle, a collection cycle, and apost-collection cycle.

During the pre-collection cycle, the set 264 is primed to vent air priorto venipuncture. During the collection cycle, whole blood drawn from thedonor is processed to collect plasma, while returning red blood cells tothe donor. During the post-collection cycle, excess plasma is returnedto the donor, and the set is flushed with saline.

1. The Pre-Collection Cycle

a. Anticoagulant Prime

In the pre-collection cycle for the plasma collection (no red bloodcells) procedure, the cassette is programmed to carry out AC Prime 1 andAC Prime 2 Phases that are identical to the AC Prime 1 and AC Prime 2Phases of the double red blood cell collection procedure.

b. Saline Prime

In the pre-collection cycle for the plasma collection (no red bloodcell) procedure, the cassette is programmed to carry out Saline Prime 1,Saline Prime 2, Saline Prime 3, Vent Donor Line, and Venipuncture Phasesthat are identical to the Saline Prime 1, Saline Prime 2, Saline Prime3, Vent Donor Line, and Venipuncture Phases of the double red blood cellcollection procedure.

The programming of the circuit during the phases of the pre-collectioncycle is summarized in the following table.

TABLE Programming of Blood Processing Circuit During Pre- CollectionPhase (Plasma Collection Procedure) Vent AC AC Saline Saline SalineDonor Veni- Phase Prime 1 Prime 2 Prime 1 Prime 2 Prime 3 Line punctureV1 • • • • • • • V2 • • • • • • • V3 ∘ ∘ • • • ∘ • V4 • • ∘ • • • • V5 •• • • • • • V6 • • • • ∘ • • V7 • • • • ∘ • • V8 • • • • • • • V9 • •∘/• ∘/• ∘/• • • Pump Pump Pump In Out Out (Stage 1) ∘ (Stage 2) V10 • •• • ∘ • • (Stage 1) ∘/• Pump Out (Stage 2) V11 ∘/• ∘ • • • ∘/• • PumpPump In Out V12 • • • • ∘ • • (Stage 1) ∘/• Pump In (Stage 2) V13 ∘/• ∘• • • ∘/• • Pump In Pump Out V14 • • ∘/• ∘/• ∘/• • • Pump In Pump InPump Out (Stage 1) ∘ (Stage 2) V15 ∘ ∘/• • • • ∘ • Pump In Pump Out V16• • • • • • • V17 • • • • • • • V18 ∘ ∘ • • • ∘ • V19 ∘ ∘ • • • ∘ • V20∘ ∘/• • • • ∘ • Pump Out Pump In V21 • • • • • • • V22 • • ∘ ∘ ∘ • • V23• • ∘ ∘ ∘ • • PP1 ▪ ▪ □ □ □ ▪ ▪ (Stage 1) PP2 ▪ ▪ ▪ ▪ □ ▪ ▪ (Stage 2)PP3 □ ▪ ▪ ▪ ▪ □ ▪ PP4 ▪ □ ▪ ▪ ▪ ▪ ▪ Caption: ∘ denotes an open valve; •denotes a closed valve; ∘/• denotes a valve opening and closing during apumping sequence; ▪ denotes an idle pump station (not in use); and □denotes a pump station in use.

2. The Collection Cycle

a. Blood Prime

With venipuncture, tube 300 leading to the phlebotomy needle 268 isopened. In a first phase of the collection cycle (Blood Prime 1), theblood processing circuit 46 is programmed to operate the donor interfacepump PP3 (i.e., in through valve V13 and out through valve V11) and theanticoagulant pump PP4 (i.e., in through valve V20 and out through valveV15) to draw anticoagulated blood through the donor tube 270 into the inprocess container 312, in the same fashion as the Blood Prime 1 Phase ofthe the double red blood cell collection procedure, as alreadydescribed.

In a next phase (Blood Prime 2), the blood processing circuit 46 isprogrammed to operate the in-process pump station PP1 to drawanticoagulated blood from the in-process container 312 through theseparation device, in the same fashion as the Blood Prime 2 Phase forthe double red blood cell collection procedure, as already described.During this phase, saline displaced by the blood is returned to thedonor.

b. Blood Separation While Drawing Whole Blood or Without Drawing WholeBlood

In a next phase of the blood collection cycle (Blood Separation WhileDrawing Whole Blood), the blood processing circuit 46 is programmed tooperate the donor interface pump station PP3 (i.e., in through valve V13and out through valve V11); the anticoagulant pump PP4 (i.e., in throughvalve V20 and out through valve V15); the in-process pump PP1 (i.e., inthrough valve V9 and out through valve V14); and the plasma pump PP2(i.e., in through valve V12 and out through valve V 10), in the samefashion as the Blood Separation While Drawing Whole Blood Phase for thedouble red blood cell collection procedure, as already described. Thisarrangement draws anticoagulated blood into the in-process container312, while conveying the blood from the in-process container 312 intothe processing chamber for separation. This arrangement also removesplasma from the processing chamber into the plasma container 304, whileremoving red blood cells from the processing chamber into the red bloodcell container 308. This phase continues until the targeted volume ofplasma is collected in the plasma collection container 304 (as monitoredby the weigh sensor) or until a targeted volume of red blood cells iscollected in the red blood cell collection container (as monitored bythe weigh sensor).

As in the double red blood cell collection procedure, if the volume ofwhole blood in the in-process container 312 reaches a predeterminedmaximum threshold before the targeted volume of either plasma or redblood cells is collected, the circuit is programmed to enter anotherphase (Blood Separation Without Drawing Whole Blood), to terminateoperation of the donor interface pump station PP3 (while also closingvalves V13, V11, V18, and V13) to terminate collection of whole blood inthe in-process container 312, while still continuing blood separation.If the volume of whole blood reaches a predetermined minimum thresholdin the in-process container 312 during blood separation, but before thetargeted volume of either plasma or red blood cells is collected, thecircuit is programmed to return to the Blood Separation While DrawingWhole Blood Phase, to thereby refill the in-process container 312. Thecircuit is programmed to toggle between the Blood Separation Phaseswhile drawing whole blood and without drawing whole blood, according tothe high and low volume thresholds for the in-process container 312,until the requisite volume of plasma has been collected, or until thetarget volume of red blood cells has been collected, whichever occursfirst.

C. Return Red Blood Cells/Saline

If the targeted volume of plasma has not been collected, the next phaseof the blood collection cycle (Return Red Blood Cells With Separation)programs the blood processing circuit 46 to operate the donor interfacepump station PP3 (i.e., in through valve V11 and out through valve V13);the in-process pump PP1 (i.e., in through valve V9 and out through valveV14); and the plasma pump PP2 (i.e., in through valve V12 and outthrough valve V10,. This arrangement conveys anticoagulated whole bloodfrom the in-process container 312 into the processing chamber forseparation, while removing plasma into the plasma container 304 and redblood cells into the red blood cell container 308. This arrangement alsoconveys red blood cells from the red blood cell container 308 to thedonor, while also mixing saline from the container 288 in line with thereturned red blood cells. The in line mixing of saline with the redblood cells raises the saline temperature and improves donor comfort.The in line mixing of saline with the red blood cells also lowers thehematocrit of the red blood cells being returned to the donor, therebyallowing a larger gauge (i.e., smaller diameter) phlebotomy needle to beused, to further improve donor comfort. This phase continues until thered blood cell container 308 is empty, as monitored by the weigh sensor.

If the volume of whole blood in the in-process container 312 reaches aspecified low threshold before the red blood cell container 308 empties,the circuit is programmed to enter another phase (Red Blood Cell ReturnWithout Separation), to terminate operation of the in-process pumpstation PP1 (while also closing valves V9, V10, V12, and V14) toterminate blood separation. The phase continues until the red blood cellcontainer 308 empties.

Upon emptying the red blood cell container 308, the circuit isprogrammed to enter another phase (Fill Donor Line), to operate thedonor interface pump station PP3 (i.e., in through valve V11 and outthrough valve V13) to draw whole blood from the in process container 312to fill the donor tube 266, thereby purge red blood cells (mixed withsaline) in preparation for another draw whole blood cycle.

The circuit is then programmed to conduct another Blood Separation WhileDrawing Whole Blood Phase, to refill the in process container 312. Thecircuit is programmed to conduct successive draw whole blood and returnred blood cells/saline cycles, as dsecribed, until the weigh sensorindicates that a desired volume of plasma has been collected in theplasma collection container 304. When the targeted volume of plasma hasbeen collected, the post-collection cycle commences.

The programming of the circuit during the phases of the collection cycleis summarized in the following table.

TABLE Programming of Blood Processing Circuit During The CollectionCycle (Plasma Collection Procedure) Blood Separation While Return RedDrawing Blood Cells/ Whole Blood Saline with (Without Separation DrawingWhole (Without Fill Phase Blood Prime 1 Blood Prime 2 Blood) Separation)Donor Line V1 • • • • ∘ V2 • • ∘ ∘ • V3 ∘ • ∘ • • (•) V4 • • • • • V5 •• ∘ ∘ (•) • V6 • • • • • V7 • ∘ • ∘/• ∘ Alternates with V23 V8 • • • • •V9 • ∘/• ∘/• ∘/• • Pump In Pump In Pump In (•) V10 • • ∘/• ∘/• • PumpOut Pump Out (•) V11 ∘/• ∘ ∘/• ∘/• ∘/• Pump Out Pump Out Pump In Pump In(•) V12 • • ∘/• ∘/• • Pump In Pump In (•) V13 ∘/• ∘ ∘/• ∘/• ∘/• Pump InPump In Pump Out Pump Out (•) V14 • ∘/• ∘/• ∘/• • Pump Out Pump Out PumpOut (•) V15 ∘/• • ∘/• • • Pump Out Pump Out (•) V16 • • • • • V17 • • •• • V18 ∘ ∘ ∘ ∘ ∘ (•) V19 ∘ • ∘ • • (•) V20 ∘/• • ∘/• • • Pump Out PumpIn (•) V21 • • • • • V22 • • • ∘ • V23 • • • ∘/• • Alternates with V7PP1 ▪ □ □ □ ▪ (▪) PP2 ▪ ▪ □ □ ▪ (▪) PP3 □ ▪ □ □ □ (▪) PP4 □ ▪ □ ▪ ▪ (▪)Caption: ∘ denotes an open valve; • denotes a closed valve; ∘/• denotesa valve opening and closing during a pumping sequence; ▪ denotes an idlepump station (not in use); and □ denotes a pump station in use.

d. The Post-Collection Cycle

Once the targeted volume of plasma has been collected (as monitored bythe weigh sensor), the circuit is programmed to carry out the phases ofthe post-collection cycle.

3. Return Excess Red Blood Cells

In a first phase of the post-collection cycle (Remove Plasma CollectionContainer), the circuit is programmed to close all valves and disableall pump stations to allow separation of the plasma collection container304 from the set 264.

In the second phase of the post-collection cycle (Return Red BloodCells), the circuit is programmed to operate the donor interface pumpstation PP3 (i.e., in through valve V11 and out through valve V13) toconvey red blood cells remaining in the red blood cell collectioncontainer 308 to the donor. The circuit is also programmed in this phaseto mix saline from the container 288 in line with the returned red bloodcells. This phase continues until the red blood cell container 308 isempty, as monitored by the weigh sensor.

4. Saline Purge

In the next phase of the post-collection cycle (Saline Purge), thecircuit is programmed to operate the donor interface pump station PP3(i.e., in through valve V11 and out through valve V11) to convey salinefrom the container 288 through the separation device, to displace theblood contents of the separation device into the in-process container312, in preparation for their return to the donor. This phase reducesthe loss of donor blood. This phase continues until a predeterminedvolume of saline in pumped through the separation device, as monitoredby the weigh sensor.

5. Final Return to Donor

In the next phase of the post-collection cycle (Final Return), thecircuit is programmed to operate the donor interface pump station PP3(i.e., in through valve V11 and out through valve V13) to convey theblood contents of the in-process container 312 to the donor. Saline isintermittently mixed with the blood contents. This phase continues untilthe in-process container 312 is empty, as monitored by the weigh sensor.

In the next phase (Fluid Replacement), the circuit is programmed tooperate the donor interface pump station PP3 (i.e., in through valve V11and out through valve V13) to convey the saline to the donor. This phasecontinues until a prescribed replacement volume amount is infused, asmonitored by the weigh sensor.

In the final phase (End Procedure), the circuit is programmed to closeall valves and idle all pump stations, so that venipuncture can beterminated, and the plasma container can be separated and removed forstorage. The remaining parts of the disposable set can be removed anddiscarded.

The programming of the circuit during the phases of the post-collectioncycle is summarized in the following table.

TABLE Programming of Blood Processing Circuit During The Post-CollectionCycle (Plasma Collection Procedure) Remove Fluid Plasma Re- CollectionReturn Saline Final place- End Phase Container RBC Purge Return mentProcedure V1 • • • ∘ • • V2 • ∘ • • • • V3 • • • • • • V4 • • ∘ • • • V5• • • • • • V6 • • • • • • V7 • ∘/• • ∘/• • • Alternates Alternates withwith V23 V23 V8 • • • • • • V9 • ∘ ∘ • • • V10 • • • • • • V11 • ∘/• ∘/•∘/• ∘/• • Pump Pump Pump Pump In In/ In In Pump Out V12 • • • • • • V13• ∘/• • ∘/• ∘/• • Pump Pump Pump Out Out Out V14 • • ∘ • • • V15 • • • •• • V16 • • • • • • V17 • • • • • • V18 • • ∘ ∘ • V19 • • • • • • V20 •• • • • • V21 • • • • • • V22 • ∘ ∘ ∘ ∘ • V23 • ∘/• ∘ ∘/• ∘ • AlternatesAlternates with with V6 V7 PP1 ▪ ▪ ▪ ▪ ▪ ▪ PP2 ▪ ▪ ▪ ▪ ▪ ▪ PP3 ▪ □ □ □ □PP4 ▪ ▪ ▪ ▪ ▪ Caption: ∘ denotes an open valve; • denotes a closedvalve; ∘/• denotes a valve opening and closing during a pumpingsequence; ▪ denotes an idle pump station (not in use) ; and □ denotes apump station in use.

G. Red Blood Cell and Plasma Collection

During this procedure, whole blood from a donor is centrifugallyprocessed to collect up to about 550 ml of plasma and up to about 250 mlof red blood cells. This procedure will, in shorthand, be called the redblood cell/plasma collection procedure.

The portion of the red blood cells not retained for collection areperiodically returned to the donor during blood separation. Plasmacollected in excess of the 550 ml target and red blood cells collectedin excess of the 250 ml target are also returned to the donor at the endof the procedure.

Programming of the blood processing circuit 46 (through the selectiveapplication of pressure to the valves and pump stations of the cassette)makes it possible to use the same universal set 264 used to carry outthe double red blood cell collection or the plasma collection procedure.

The procedure includes a pre-collection cycle, a collection cycle, and apost-collection cycle, and a storage preparation cycle.

During the pre-collection cycle, the set 264 is primed to vent air priorto venipuncture. During the collection cycle, whole blood drawn from thedonor is processed to collect plasma and red blood cells, whilereturning a portion of the red blood cells to the donor. During thepost-collection cycle, excess plasma and red blood cells are returned tothe donor, and the set is flushed with saline. During the storagepreparation cycle, a red blood cell storage solution added to thecollected red blood cells.

(1) The Pre-Collection Cycle

a. Anticoagulant Prime

In the pre-collection cycle for the red blood cell/plasma collectionprocedure, the cassette is programmed to carry out AC Prime 1 and ACPrime 2 Phases that are identical to the AC Prime 1 and AC Prime 2Phases of the double red blood cell collection procedure.

b. Saline Prime

In the pre-collection cycle for the red blood cell/plasma collectionprocedure, the cassette is programmed to carry out Saline Prime 1,Saline Prime 2 , Saline Prime 3, Vent Donor Line, and VenipuncturePhases that are identical to the Saline Prime 1, Saline Prime 2, SalinePrime 3, Vent Donor Line, and Venipuncture Phases of the double redblood cell collection procedure.

The programming of the circuit during the phases of the pre-collectioncycle is summarized in the following table.

TABLE Programming of Blood Processing Circuit During Pre- CollectionCycle (Red Blood Cell/Plasma Collection Procedure) Vent AC AC SalineSaline Saline Donor Veni- Phase Prime 1 Prime 2 Prime 1 Prime 2 Prime 3Line puncture V1 • • • • • • • V2 • • • • • • • V3 ∘ ∘ • • • ∘ • V4 • •∘ • • • • V5 • • • • • • • V6 • • • • ∘ • • V7 • • • • ∘ • • V8 • • • •• • • V9 • • ∘/• ∘/• ∘/• • • Pump Pump Pump In Out Out (Stage 1) ∘(Stage 2) V10 • • • • ∘ • • (Stage 1) ∘/• Pump Out (Stage 2) V11 ∘/• ∘ •• • ∘/• • Pump Pump In Out V12 • • • • ∘ • • (Stage 1) ∘/• Pump In(Stage 2) V13 ∘/• ∘ • • • ∘/• • Pump In Pump Out V14 • • ∘/• ∘/• ∘/• • •Pump In Pump In Pump Out (Stage 1) ∘ (Stage 2) V15 ∘ ∘/• • • • ∘ • PumpIn Pump Out V16 • • • • • • • V17 • • • • • • • V18 ∘ ∘ • • • ∘ • V19 ∘∘ • • • ∘ • V20 ∘ ∘/• • • • ∘ • Pump Out Pump In V21 • • • • • • • V22 •• ∘ ∘ ∘ • • V23 • • ∘ ∘ ∘ • • PP1 ▪ ▪ □ □ □ ▪ ▪ (Stage 1) PP2 ▪ ▪ ▪ ▪ □▪ ▪ (Stage 2) PP3 □ ▪ ▪ ▪ ▪ □ ▪ PP4 ▪ □ ▪ ▪ ▪ ▪ ▪ Caption: ∘ denotes anopen valve; • denotes a closed valve; ∘/• denotes a valve opening andclosing during a pumping sequence; ▪ denotes an idle pump station (notin use); and □ denotes a pump station in use.

2. The Collection Cycle

a. Blood Prime

With venipuncture, tube 300 leading to the phlebotomy needle 268 isopened. The collection cycle of the red blood cell/plasma collectionprocedure programs the circuit to carry out Blood Prime 1 and BloodPrime 2 Phases that are identical to the Blood Prime 1 and Blood Prime 2Phases of the Double Red Blood Cell Collection Procedure, alreadydescribed.

b. Blood Separation While Drawing Whole Blood or Without Drawing WholeBlood

In the blood collection cycle for the red blood cell/plasma collectionprocedure, the circuit is programmed to conduct a Blood Separation WhileDrawing Whole Blood Phase, in the same fashion that the Blood SeparationWhile Drawing Whole Blood Phase is conducted for the double red bloodcell collection procedure. This arrangement draws anticoagulated bloodinto the in-process container 312, while conveying the blood from thein-process container 312 into the processing chamber for separation.This arrangement also removes plasma from the processing chamber intothe plasma container 304, while removing red blood cells from theprocessing chamber into the red blood cell container 308. This phasecontinues until the desired maximum volumes of plasma and red bloodcells have been collected in the plasma and red blood cell collectioncontainers 304 and 308 (as monitored by the weigh sensor).

As in the double red blood cell collection procedure and the plasmacollection procedure, if the volume of whole blood in the in-processcontainer 312 reaches a predetermined maximum threshold before thetargeted volume of either plasma or red blood cells is collected, thecircuit is programmed to enter a phase (Blood Separation Without WholeBlood Draw) to terminate operation of the donor interface pump stationPP3 (while also closing valves V13, V11, V18, and V13) to terminatecollection of whole blood in the in-process container 312, while stillcontinuing blood separation. If the volume of whole blood reaches apredetermined minimum threshold in the in-process container 312 duringblood separation, but before the targeted volume of either plasma or redblood cells is collected, the circuit is programmed to return to theBlood Separation With Whole Blood Draw, to thereby refill the in-processcontainer 312. The circuit is programmed to toggle between the BloodSeparation cycle with whole blood draw and without whole blood drawaccording to the high and low volume thresholds for the in-processcontainer 312, until the requisite maximum volumes of plasma and redblood cells have been collected.

c. Return Red Blood Cells and Saline

If the targeted volume of plasma has not been collected, and red bloodcells collected in the red blood cell container 308 exceed apredetermined maximum threshold, the next phase of the blood collectioncycle (Return Red Blood Cells With Separation) programs the bloodprocessing circuit 46 to operate the donor interface pump station PP3(i.e., in through valve V11 and out through valve V13); the in-processpump PP1 (i.e., in through valve V9 and out through valve V14); and theplasma pump PP2 (i.e., in through valve V12 and out through valve V10,.This arrangement continues to convey anticoagulated whole blood from thein-process container 312 into the processing chamber for separation,while removing plasma into the plasma container 304 and red blood cellsinto the red blood cell container 308. This arrangement also conveys allor a portion of the red blood cells collected in the red blood cellcontainer 308 to the donor. This arrangement also mixes saline from thecontainer 288 in line with the returned red blood cells. The in linemixing of saline with the red blood cells raises the saline temperatureand improves donor comfort. The in line mixing of saline with the redblood cells also lowers the hematocrit of the red blood cells beingreturned to the donor, thereby allowing a larger gauge (i.e., smallerdiameter) phlebotomy needle to be used, to further improve donorcomfort.

This phase can continue until the red blood cell container 308 is empty,as monitored by the weigh sensor, thereby corresponding to the ReturnRed Blood Cells With Separation Phase of the plasma collectionprocedure. Preferably, however, the processor determines how muchadditional plasma needs to be collected to meet the plasma targetvolume. From this, the processor derives the incremental red blood cellvolume associated with the incremental plasma volume. In thisarrangement, the processor returns a partial volume of red blood cellsto the donor, so that, upon collection of the next incremental red bloodcell volume, the total volume of red blood cells in the container 308will be at or slightly over the targeted red blood cell collectionvolume.

If the volume of whole blood in the in-process container 312 reaches aspecified low threshold before return of the desired volume of red bloodcells, the circuit is programmed to enter a phase (Return Red BloodCells Without Separation), to terminate operation of the in-process pumpstation PP1 (while also closing valves V9, V10, V12, and V14) toterminate blood separation. This phase corresponds to the Return RedBlood Cells Without Separation Phase of the plasma collection procedure.

Upon returning the desired volume of red blood cells from the container308, the circuit is programmed to enter a phase (Fill Donor Line), tooperate the donor interface pump station PP3 (i.e., in through valve V11and out through valve V13) to draw whole blood from the in processcontainer 312 to fill the donor tube 266, thereby purge red blood cells(mixed with saline) in preparation for another draw whole blood cycle.

The circuit is then programmed to conduct another Blood Separation WhileDrawing Whole Blood Phase, to refill the in process container 312. Ifrequired, the circuit is capable of performing successive draw wholeblood and return red blood cells cycles, until the weigh sensorsindicate that volumes of red blood cells and plasma collected in thecontainers 304 and 308 are at or somewhat greater than the targetedvalues. The post-collection cycle then commences.

The programming of the circuit during the phases of the collection cycleis summarized in the following table.

TABLE Programming of Blood Processing Circuit During The CollectionCycle (Red Blood Cell/Plasma Collection Procedure) Blood SeparationWhile Return Red Drawing Blood Cells/ Whole Blood Saline with (WithoutSeparation Drawing Whole (Without Fill Phase Blood Prime 1 Blood Prime 2Blood) Separation) Donor Line V1 • • • • ∘ V2 • • ∘ ∘ • V3 ∘ • ∘ • • (•)V4 • • • • • V5 • • ∘ ∘ (•) • V6 • • • • • V7 • ∘ • ∘/• ∘ Alternateswith V23 V8 • • • • • V9 • ∘/• ∘/• ∘/• • Pump In Pump In Pump In (•) V10• • ∘/• ∘/• • Pump Out Pump Out (•) V11 ∘/• ∘ ∘/• ∘/• ∘/• Pump Out PumpOut Pump In Pump In (•) V12 • • ∘/• ∘/• • Pump In Pump In (•) V13 ∘/• ∘∘/• ∘/• ∘/• Pump In Pump In Pump Out Pump Out (•) V14 • ∘/• ∘/• ∘/• •Pump Out Pump Out Pump Out (•) V15 ∘/• • ∘/• • • Pump Out Pump Out (•)V16 • • • • • V17 • • • • • V18 ∘ ∘ ∘ ∘ ∘ (•) V19 ∘ • ∘ • • (•) V20 ∘/•• ∘/• • • Pump Out Pump In (•) V21 • • • • • V22 • • • ∘ • V23 • • • ∘/•• Alternates with V7 PP1 ▪ □ □ □ ▪ (▪) PP2 ▪ ▪ □ □ ▪ (▪) PP3 □ ▪ □ □ □(▪) PP4 □ ▪ □ ▪ ▪ (▪) Caption: ∘ denotes an open valve; • denotes aclosed valve; ∘/• denotes a valve opening and closing during a pumpingsequence; ▪ denotes an idle pump station (not in use); and □ denotes apump station in use.

d. The Post-Collection Cycle

Once the targeted maximum volumes of plasma and red blood cells havebeen collected (as monitored by the weigh sensor), the circuit isprogrammed to carry out the phases of the post-collection cycle.

i. Return Excess Plasma

If the volume of plasma collected in the plasma collection container 304is over the targeted volume, a phase of the post-collection cycle(Excess Plasma Return) is entered, during which the circuit isprogrammed to terminate the supply and removal of blood to and from theprocessing chamber, while operating the donor interface pump station PP3(i.e., in through valve V11 and out through valve V13) to convey plasmain the plasma container 304 to the donor. The circuit is also programmedin this phase to mix saline from the container 288 in line with thereturned plasma. This phase continues until the volume of plasma in theplasma collection container 304 is at the targeted value, as monitoredby the weigh sensor.

ii. Return Excess Red Blood Cells

If the volume of red blood cells collected in the red blood cellcollection container 308 is also over the targeted volume, a phase ofthe post-collection cycle (Excess RBC Return) is-entered, during whichthe circuit is programmed to operate the donor interface pump stationPP3 (i.e., in through valve V11 and out through valve V13) to convey redblood cells remaining in the red blood cell collection container 308 tothe donor. The circuit is also programmed in this phase to mix salinefrom the container 288 in line with the returned red blood cells. Thisphase continues until the volume of red blood cells in the container 308equals the targeted value, as monitored by the weigh sensor.

iii. Saline Purge

When the volumes of red blood cells and plasma collected in thecontainers 308 and 304 equal the targeted values, the next phase of thepost-collection cycle (Saline Purge) is entered, during which thecircuit is programmed to operate the donor interface pump station PP3(i.e., in through valve V11 and out through valve V11) to convey salinefrom the container 288 through the separation device, to displace theblood contents of the separation device into the in-process container312, in preparation for their return to the donor. This phase reducesthe loss of donor blood. This phase continues until a predeterminedvolume of saline in pumped through the separation device, as monitoredby the weigh sensor.

iv. Final Return to Donor

In the next phase of the post-collection cycle (Final Return), thecircuit is programmed to operate the donor interface pump station PP3(i.e., in through valve V11 and out through valve V13) to convey theblood contents of the in-process container 312 to the donor. Saline isintermittently mixed with the blood contents. This phase continues untilthe in-process container 312 is empty, as monitored by the weigh sensor.

In the next phase (Fluid Replacement), the circuit is programmed tooperate the donor interface pump station PP3 (i.e., in through valve V11and out through valve V13) to convey the saline to the donor. This phasecontinues until a prescribed replacement volume amount is infused, asmonitored by the weigh sensor.

In the next phase (End Venipuncture), the circuit is programmed to closeall valves and idle all pump stations, so that venipuncture can beterminated.

The programming of the circuit during the phases of the post-collectioncycle is summarized in the following table.

TABLE Programming of Blood Processing Circuit During The Post-CollectionCycle (Red Blood Cell/Plasma Collection Procedure) Excess Plasma ExcessRBC Saline Final Fluid End Phase Return Return Purge Return ReplacementVenipuncture V1 • • • ∘ • • V2 • ∘ • • • • V3 • • • • • • V4 • • ∘ • • •V5 ∘ • • • • • V6 ∘/• • • • • • Alternates with V23 V7 • ∘/• • ∘/• • •Alternates Alternates with V23 with V23 V8 • • • • • • V9 ∘ ∘ ∘ • • •V10 • • • • • • V11 ∘/• ∘/• ∘/• ∘/• ∘/• • Pump In Pump In Pump Pump InPump In In/ Pump Out V12 • • • • • • V13 ∘/• ∘/• • ∘/• ∘/• • Pump OutPump Out Pump Out Pump Out V14 • • ∘ • • • V15 • • • • • • V16 • • • • •• V17 • • • • • • V18 ∘ • ∘ ∘ • V19 • • • • • • V20 • • • • • • V21 • •• • • • V22 ∘ ∘ ∘ ∘ ∘ • V23 ∘/• ∘/• ∘ ∘/• ∘ • Alternates AlternatesAlternates with V6 with V6 with V7 PP1 ▪ ▪ ▪ ▪ ▪ ▪ PP2 ▪ ▪ ▪ ▪ ▪ ▪ PP3 □□ □ □ □ ▪ PP4 ▪ ▪ ▪ ▪ ▪ ▪ Caption: ∘ denotes an open valve; • denotes aclosed valve; ∘/• denotes a valve opening and closing during a pumpingsequence; ▪ denotes an idle pump station (not in use) ; and □ denotes apump station in use.

e. The Storage Preparation Cycle

i. RBC Preservative Prime

In the first phase of the storage preparation cycle (Prime StorageSolution), the circuit is programmed to operate the donor interface pumpstation PP3 to transfer a desired volume of red blood cell storagesolution from the container 280 into the in-process container 312. Thetransfer of the desired volume is monitored by the weigh scale.

In the next phase (Transfer Storage Solution), the circuit is programmedto operate the donor interface pump station PP3 to transfer a desiredvolume of red blood cell storage solution from the in-process container312 into the red blood cell collection container 308. The transfer ofthe desired volume is monitored by the weigh scale.

In the next and final phase (End Procedure), the circuit is programmedto close all valves and idle all pump stations, so that the plasma andred blood cell storage containers 304 and 308 can be separated andremoved for storage. The remainder of the disposable set can now beremoved and discarded.

The programming of the circuit during the phases of the storagepreparation cycle is summarized in the following table.

TABLE Programming of Blood Processing Circuit During The StoragePreparation Cycle (Red Blood Cell/Plasma Collection Procedure) PrimeStorage Transfer Storage Phase Solution Solution End Procedure V1 • • •V2 • ∘ • V3 ∘ • • V4 • ∘ • V5 • • • V6 • • • V7 • • • V8 • • • V9 • • •V10 • • • V11 ∘/• ∘/• • Pump In/ Pump In/ Pump Out Pump Out V12 • • •V13 • • • V14 • • • V15 • • • V16 ∘ ∘ • V17 • • • V18 • • • V19 • • •V20 • • • V21 ∘ ∘ • V22 • • • V23 • • • PP1 ▪ ▪ ▪ PP2 ▪ ▪ ▪ PP3 □ □ ▪PP4 ▪ ▪ ▪ Caption: ∘ denotes an open valve; • denotes a closed valve;∘/• denotes a valve opening and closing during a pumping sequence; ▪denotes an idle pump station (not in use); and □ denotes a pump stationin use.V. Interface Control

A. Underspill and Overspill Detection

In any of the above-described procedures, the centrifugal forces presentwithin the processing chamber 18 separate whole blood into a region ofpacked red blood cells and a region of plasma (see FIG. 15A). Thecentrifugal forces cause the region of packed red blood cells tocongregate along the outside or high-G wall of the chamber, while theregion of plasma is transported to the inside or low-G wall of thechamber.

An intermediate region forms an interface between the red blood cellregion and the plasma region. Intermediate density cellular bloodspecies like platelets and leukocytes populate the interface, arrangedaccording to density, with the platelets closer to the plasma layer thanthe leukocytes. The interface is also called the “buffy coat,” becauseof its cloudy color, compared to the straw color of the plasma regionand the red color of the red blood cell region.

It is desirable to monitor the location of the buffy coat, either tokeep the buffy coat materials out of the plasma or out of the red bloodcells, depending on the procedure, or to collect the cellular contentsof the buffy coat. The system includes a sensing station 332 comprisingtwo optical sensors 334 and 336 for this purpose.

In the illustrated and preferred embodiment (see FIG. 13), the sensingstation 332 is located a short distance outside the centrifuge station20. This arrangement minimizes the fluid volume of components leavingthe chamber before monitoring by the sensing station 332.

The first sensor 334 in the station 332 optically monitors the passageof blood components through the plasma collection tube 292. The secondsensor 336 in the station 332 optically monitors the passage of bloodcomponents through the red blood cell collection tube 294.

The tubes 292 and 294 are made from plastic (e.g. polyvinylchloride)material that is transparent to the optical energy used for sensing, atleast in the region where the tubes 292 and 294 are to be placed intoassociation with the sensing station 332.

In the illustrated embodiment, the set 264 includes a fixture 338 (seeFIGS. 16 to 18) to hold the tubes 292 and 294 in viewing alignment withits respective sensor 334 and 336. The fixture 338 gathers the tubes 292and 294 in a compact, organized, side-by-side array, to be placed andremoved as a group in association with the sensors 334 and 336, whichare also arranged in a compact, side-by-side relationship within thestation 332.

In the illustrated embodiment, the fixture 338 also holds the tube 290,which conveys whole blood into the centrifuge station 20, even though noassociated sensor is provided. The fixture 338 serves to gather and holdall tubes 290, 292, and 294 that are coupled to the umbilicus 296 in acompact and easily handled bundle.

The fixture 338 can be an integral part of the umbilicus 296, formed,e.g., by over molding. Alternatively, the fixture 338 can be aseparately fabricated part, which snap fits about the tubes 290, 292,and 294 for use.

In the illustrated embodiment (as FIG. 2 shows), the containers 304,308, and 312 coupled to the cassette 28 are suspended during use abovethe centrifugation station 20. In this arrangement, the fixture 338directs the tubes 290, 292, and 294 through an abrupt, ninety degreebend immediately beyond the end of the umbilicus 296 to the cassette 28.The bend imposed by the fixture 338 directs the tubes 290, 292, and 294in tandem away from the area immediately beneath the containers 304,308, and 312, thereby preventing clutter in this area. The presence ofthe fixture 338 to support and guide the tubes 290, 292, and 294 throughthe bend also reduces the risk of kinking or entanglement.

The first sensor 334 is capable of detecting the presence of opticallytargeted cellular species or components in the plasma collection tube292. The components that are optically targeted for detection varydepending upon the procedure.

For a plasma collection procedure, the first sensor 334 detects thepresence of platelets in the plasma collection tube 292, so that controlmeasures can be initiated to move the interface between the plasma andplatelet cell layer back into the processing chamber. This provides aplasma product that can be essentially platelet-free or at least inwhich the number of platelets is minimized.

For a red blood cell-only collection procedure, the first sensor 334detects the interface between the buffy coat and the red blood celllayer, so that control measures can be initiated to move this interfaceback into the processing chamber. This maximizes the red blood cellyield.

For a buffy coat collection procedure (which will be described later),the first sensor 334 detects when the leading edge of the buffy coat(i.e., the plasma/platelet interface) begins to exit the processingchamber, as well as detects when the trailing edge of the buffy coat(i.e., the buffy coat/red blood cell interface) has completely exitedthe processing chamber.

The presence of these cellular components in the plasma, as detected bythe first sensor 334, indicates that the interface is close enough tothe low-G wall of the processing chamber to allow all or some of thesecomponents to be swept into the plasma collection line (see FIG. 15B).This condition will also be called an “over spill.”

The second sensor 336 is capable of detecting the hematocrit of the redblood cells in the red blood cell collection tube 294. The decrease ofred blood hematocrit below a set minimum level during processing thatthe interface is close enough to the high-G wall of the processingchamber to allow plasma to enter the red blood cell collection tube 294(see FIG. 15C). This condition will also be called an “under spill.”

B. The Sensing Circuit

The sensing station 332 includes a sensing circuit 340 (see FIG. 19), ofwhich the first sensor 334 and second sensor 336 form a part.

The first sensor 334 includes one green light emitting diode (LED) 350,one red LED 352, and two photodiodes 354 and 355. The photodiode 354measures transmitted light, and the photodiode 355 measures reflectedlight.

The second sensor 336 includes one red LED 356 and two photodiodes 358and 360. The photodiode 358 measures transmitted light, and thephotodiode 360 measures reflected light.

The sensing circuit 340 further includes an LED driver component 342.The driver component 342 includes a constant current source 344, coupledto the LED's 350, 352, and 356 of the sensors 334 and 336. The constantcurrent source 344 supplies a constant current to each LED 350, 352, and356, independent of temperature and the power supply voltage levels. Theconstant current source 344 thereby provides a constant output intensityfor each LED 350, 352, and 356.

The LED drive component 342 includes a modulator 346. The modulator 346modulates the constant current at a prescribed frequency. The modulation346 removes the effects of ambient light and electromagneticinterference (EMI) from the optically sensed reading, as will bedescribed in greater detail later.

The sensing circuit 340 also includes a receiver circuit 348 coupled tothe photodiodes 354, 355, 358, and 360. The receiver circuit 348includes, for each photodiode 354, 355, 358, and 360, a dedicatedcurrent-to-voltage (I-V) converter 362. The remainder of the receivercircuit 348 includes a bandpass filter 364, a programmable amplifier366, and a full wave rectifier 368. These components 364, 366, and 368are shared, e.g., using a multiplexer.

Ambient light typically contains frequency components less than 1000 Hz,and EMI typically contains frequency components above 2 Khz. With thisin mind, the modulator 346 modulates the current at a frequency belowthe EMI frequency components, e.g., at about 2 Khz. The bandpass filter364 has a center frequency of about the same value, i.e., about 2 Khz.The sensor circuit 340 eliminates frequency components above and belowthe ambient light source and EMI components from the sensed measurement.In this way, the sensing circuit 340 is not sensitive to ambientlighting conditions and EMI.

More particularly, transmitted or reflected light from the tube 292 or294 containing the fluid to be measured is incident on photodiodes 354and 355 (for the tube 292) or photodiodes 358 and 360 (for tube 294).Each photodiode produces a photocurrent proportional to the receivedlight intensity. This current is converted to a voltage. The voltage isfed, via the multiplexer 370, to the bandpass filter 364. The bandpassfilter 364 has a center frequency at the carrier frequency of themodulated source light (i.e., 2 Khz in the illustrated embodiment).

The sinusoidal output of the bandpass filter 364 is sent to the variablegain amplifier 366. The gain of the amplifier is preprogrammed inpreestablished steps, e.g., ×1, ×10, ×100, and ×1000. This provides theamplifier with the capability to respond to a large dynamic range.

The sinusoidal output of the amplifier 366 is sent to the full waverectifier 368, which transforms the sinusoidal output to a DC outputvoltage proportional to the transmitted light energy.

The controller 16 generates timing pulses for the sensor circuit 340.The timing pulses comprise, for each LED, (i) a modulation square waveat the desired modulation frequency (i.e., 2 Khz in the illustratedembodiment), (ii) an enable signal, (iii) two sensor select bits (whichselect the sensor output to feed to the bandpass filter 364), and (iv)two bits for the receiver circuit gain selection (for the amplifier366).

The controller 16 conditions the driver circuit 342 to operate each LEDin an ON state and an OFF state.

In the ON state, the LED enable is set HIGH, and the LED is illuminatedfor a set time interval, e.g., 100 ms. During the first 83.3 ms of theON state, the finite rise time for the incident photodiode and receivercircuit 348 are allowed to stabilize. During the final 16.7 ms of the ONstate, the output of the circuit 340 is sampled at twice the modulationrate (i.e., 4 Khz in the illustrated embodiment). The sampling intervalis selected to comprises one complete cycle of 60 Hz, allowing the mainfrequency to be filtered from the measurement. The 4 Khz samplingfrequency allows the 2 Khz ripple to be captured for later removal fromthe measurement.

During the OFF state, the LED is left dark for 100 ms. The LED baselinedue to ambient light and electromagnetic interference is recorded duringthe final 16.7 ms.

1. The First Sensor: Platelet/RBC Differentiation

In general, cell free (“free”) plasma has a straw color. As theconcentration of platelets in the plasma increases, the clarity of theplasma decreases. The plasma looks “cloudy.” As the concentration of redblood cells in the plasma increases, the plasma color turns from strawto red.

The sensor circuit 340 includes a detection/differentiation module 372,which analyses sensed attenuations of light at two different wavelengthsfrom the first sensor 334 (using the transmitted light sensingphotodiode 354). The different wavelengths are selected to possessgenerally the same optical attenuation for platelets, but significantlydifferent optical attentuations for red blood cells.

In the illustrated embodiment, the first sensor 334 includes an emitter350 of light at a first wavelength (λ₁), which, in the illustratedembodiment, is green light (570 nm and 571 nm). The first sensor 334also includes an emitter 352 of light at a second wavelength (λ₂),which, in the illustrated embodiment, is red light (645 nm to 660 nm).

The optical attenuation for platelets at the first wavelength(ε_(platelets) ^(λ) ₁) and the optical attenuation for platelets at thesecond wavelength (Ε_(platelets) ^(λ) ₂) are generally the same. Thus,changes in attenuation over time, as affected by increases or decreasesin platelet concentration, will be similar.

However, the optical attenuation for hemoglobin at the first wavelength(ε_(Hb) ^(λ) ₁) is about ten times greater than the optical attenuationfor hemoglobin at the second wavelength (ε_(Hb) ^(λ) ₂). Thus, changesin attenuation over time, as affected by the presence of red bloodcells, will not be similar.

The tube 294, through which plasma to be sensed, is transparent to lightat the first and second wavelengths. The tube 294 conveys the plasmaflow past the first and second emitters 350 and 352.

The light detector 354 receives light emitted by the first and secondemitters 350 and 352 through the tube 294. The detector 354 generatessignals proportional to intensities of received light. The intensitiesvary with optical attenuation caused by the presence of platelets and/orred blood cells.

The module 372 is coupled to the light detector 354 to analyze thesignals to derive intensities of the received light at the first andsecond wavelengths. The module 372 compares changes of the intensitiesof the first and second wavelengths over time. When the intensities ofthe first and second wavelengths change over time in substantially thesame manner, the module 372 generates an output representing presence ofplatelets in the plasma flow. When the intensities of the first andsecond wavelengths change over time in a substantially different manner,the module 372 generates an output representing presence of red bloodcells in the plasma flow. The outputs therefore differentiate betweenchanges in intensity attributable to changes in platelet concentrationin the plasma flow and changes in intensity attributable to changes inred blood cell concentration in the plasma flow.

There are various ways to implement the module 372. In a preferredembodiment, the detection/differentiation module 372 considers that theattenuation of a beam of monochromatic light of wavelength λ by a plasmasolution can be described by the modified Lambert-Beer law, as follows:

$\begin{matrix}{I = {I_{O}e^{- {\lbrack{{{({{ɛ_{Hb}^{\lambda}c_{Hb}H} + {ɛ_{platelets}^{\lambda}c_{platelets}}})}d} + G_{platelets}^{\lambda} + G_{RBC}^{\lambda}}\rbrack}}}} & (1)\end{matrix}$

where:

I is transmitted light intensity.

I_(o) is incident light intensity.

ε_(Hb) ^(λ) is the optical attenuation of hemoglobin (Hb) (gm/dl) at theapplied wavelength.

ε_(platelets) ^(λ) is the optical attenuation of platelets at theapplied wavelength.

C_(Hb) is the concentration of hemoglobin in a red blood cell, taken tobe 34 gm/dl.

C_(platelets) is the concentration of platelets in the sample.

d is thickness of the plasma stream through the tube 294.

G^(λ) is the path length factor at the applied wavelength, whichaccounts for additional photon path length in the plasma sample due tolight scattering.

H is whole blood hematocrit, which is percentage of red blood cells inthe sample.

G_(RBC) ^(λ) and G_(platelets) ^(λ) are a function of the concentrationand scattering coefficients of, respectively, red blood cells andplatelets at the applied wavelengths, as well as the measurementgeometry.

For wavelengths in the visible and near infrared spectrum, ε_(platelets)^(λ)≈0, therefore:

$\begin{matrix}{{{Ln}\left( \frac{I^{\lambda}}{I_{O}^{\lambda}} \right)} = {{{Ln}\left( T^{\lambda} \right)} \approx {- \left\lbrack {{\left( {ɛ_{Hb}^{\lambda}C_{Hb}H} \right)d} + G_{platelets}^{\lambda} + G_{RBC}^{\lambda}} \right\rbrack}}} & (2)\end{matrix}$

In an over spill condition (shown in FIG. 15B), the first cellularcomponent to be detected by the first sensor 334 in the plasmacollection line 294 will be platelets. Therefore, for the detection ofplatelets, Ln(T^(λ))≈G_(platelets) ^(λ).

To detect the buffy coat interface between the platelet layer and thered blood cell layer, the two wavelengths (λ₁ and λ₂) are chosen basedupon the criteria that (i) λ₁ and λ₂ have approximately the same pathlength factor (G^(λ)), and (ii) one wavelength λ₁ or λ₂ has a muchgreater optical attenuation for hemoglobin than the other wavelength.

Assuming the wavelengths λ₁ and λ₂ have the same G^(λ), Equation (2)reduces to:

$\begin{matrix}{{{{Ln}\left( T^{\lambda_{1}} \right)} - {{Ln}\left( T^{\lambda_{2}} \right)}} \approx {{Hdc}_{Hb}\left( {ɛ_{Hb}^{\lambda_{2}} - ɛ_{Hb}^{\lambda_{1}}} \right)}} & (3)\end{matrix}$

In the preferred embodiment, λ₁=660 nm (green) and λ₂=571 nm (red). Thepath length factor (G^(λ)) for 571 nm light is greater than for 660 nmlight. Therefore the path length factors have to be modified bycoefficients α and β, as follows:

$\begin{matrix}{G_{RBC}^{\lambda_{1}} = {\alpha\; G_{RBC}^{\lambda_{2}}}} \\{G_{platelets}^{\lambda_{1}} = {\beta\; G_{platelets}^{\lambda_{2}}}}\end{matrix}$

Therefore, Equation (3) can be reexpressed as follows:

$\begin{matrix}\begin{matrix}{{{{Ln}\left( T^{\lambda_{1}} \right)} - {{Ln}\left( T^{\lambda_{2}} \right)}} \approx {{{Hdc}_{Hb}\left( {ɛ_{Hb}^{\lambda_{2}} - ɛ_{Hb}^{\lambda_{1}\;}} \right)} +}} \\{{\left( {\alpha - 1} \right)G_{RBC}^{\lambda_{1}}} + {\left( {\beta - 1} \right)G_{platelets}^{\lambda_{2}}}}\end{matrix} & (4)\end{matrix}$

In the absence of red blood cells, Equation (3) causes a false red bloodcell detect with increasing platelet concentrations, as Equation (5)demonstrates:

$\begin{matrix}{{{{Ln}\left( T^{\lambda_{1}} \right)} - {{Ln}\left( T^{\lambda_{2}} \right)}} = {\left( {\beta - 1} \right)G_{platelets}^{\lambda_{1}}}} & (5)\end{matrix}$

For the detection of platelets and the interface between theplatelet/red blood cell layer, Equation (4) provides a betterresolution. The module 372 therefore applies Equation (4). Thecoefficient (β−1) can be determined by empirically measuring

G_(platelets)^(λ₁)  and  G_(platelets)^(λ₂)in the desired measurement geometry for different known concentrationsof platelets in prepared platelet-spiked plasma.

The detection/differentiation module 372 also differentiates betweenintensity changes due to the presence of red blood cells in the plasmaor the presence of free hemoglobin in the plasma due to hemolysis. Bothcircumstances will cause a decrease in the output of the transmittedlight sensing photodiode 354. However, the output of the reflected lightsensing photodiode 355 increases in the presence of red blood cells anddecreases in the presence of free hemoglobin. Thedetection/differentiation module 372 thus senses the undesiredoccurrence of hemolysis during blood processing, so that the operatorcan be alerted and corrective action can be taken.

2. The Second Sensor: Packed Red Blood Cell Measurement

In an under spill condition (shown in FIG. 15C), the hematocrit of redblood cells exiting the processing chamber 18 will dramaticallydecrease, e.g., from a targeted hematocrit of about 80 to a hematocritof about 50, as plasma (and the buffy coat) mixes with the red bloodcells. An under spill condition is desirable during a plasma collectionprocedure, as it allows the return of the buffy coat to the donor withthe red blood cells. An under spill condition is not desired during ared blood cell-only collection procedure, as it jeopardizes the yieldand quality of red blood cells that are collected for storage.

In either situation, the ability to sense when an under spill conditionexists is desireable.

Photon wavelengths in the near infrared spectrum (NIR) (approximately540 nm to 1000 nm) are suitable for sensing red blood cells, as theirintensity can be measured after transmission through many millimeters ofblood.

The sensor circuit 340 includes a red blood cell detection module 374.The detection module 374 analyses sensed optical transmissions of thesecond sensor 336 to discern the hematocrit and changes in thehematocrit of red blood cells exiting the processing chamber 18.

The detection module 374 considers that the attenuation of a beam ofmonochromatic light of wavelength λ by blood may be described by themodified Lambert-Beer law, as follows:

$\begin{matrix}{I = {I_{o}{\mathbb{e}}^{- {\lbrack{{{({ɛ_{Hb}^{\lambda}c_{Hb}H})}d} + G_{RBC}^{\lambda}}\rbrack}}}} & (6)\end{matrix}$

where:

I is transmitted light intensity.

I_(o) is incident light intensity.

ε_(Hb) ^(λ) is the extinction coefficient of hemoglobin (Hb) (gm/dl) atthe applied wavelength.

C_(Hb) is the concentration of hemoglobin in a red blood cell, taken tobe 34 gm/dl.

d is the distance between the light source and light detector.

G^(λ) is the path length factor at the applied wavelength, whichaccounts for additional photon path length in the media due to lightscattering.

H is whole blood hematocrit, which is percentage of red blood cells inthe sample.

G_(RBC) ^(λ) is a function of the hematocrit and scattering coefficientsof red blood cells at the applied wavelengths, as well as themeasurement geometry.

Given Equation (6), the optical density O.D. of the sample can beexpressed as follows:

$\begin{matrix}{{{Ln}\left( \frac{I^{\lambda}}{I_{o}^{\lambda}} \right)} = {{O.D.} \approx {- \left\lbrack {{\left( {ɛ_{Hb}^{\lambda}C_{Hb}H} \right)d} + G_{RBC}^{\lambda}} \right\rbrack}}} & (7)\end{matrix}$

The optical density of the sample can further be expressed as follows:O.D.=O.D. _(Absorption) +O.D. _(Scattering)  (8)

where:

O.D._(Absorption) is the optical density due to absorption by red bloodcells, expressed as follows:

$\begin{matrix}{{{O.D}._{Absorption}} = {{- \left( {ɛ_{Hb}^{\lambda}C_{Hb}H} \right)}d}} & (9)\end{matrix}$

O.D._(Scattering) is the optical density due to scattering of red bloodcells, expressed as follows:

$\begin{matrix}{{{O.D}._{Scattering}} = G_{RBC}^{\lambda}} & (10)\end{matrix}$

From Equation (9), O.D._(Absorption) increases linearly with hematocrit(H). For transmittance measurements in the red and NIR spectrum, G_(RBC)^(λ) is generally parabolic, reaching a maximum at a hematocrit ofbetween 50 and 75 (depending on illumination wavelength and measurementgeometry) and is zero at hematocrits of 0 and 100 (see, e.g., Steinke etal., “Diffusion Model of the Optical Absorbance of Whole Blood,” J. Opt.Soc. Am., Vol 5, No. 6, June 1988). Therefore, for light transmissionmeasurements, the measured optical density is a nonlinear function ofhematocrit.

Nevertheless, it has been discovered that G_(RBC) ^(λ) for reflectedlight measured at a predetermined radial distance from the incidentlight source is observed to remain linear for the hematocrit range of atleast 10 to 90. Thus, with the second sensor 336 so configured, thedetection module can treat the optical density of the sample for thereflected light to be a linear function of hematocrit. The samerelationship exists for the first sensor 334 with respect to thedetection of red blood cells in plasma.

This arrangement relies upon maintaining straightforward measurementgeometries. No mirrors or focusing lenses are required. The LED orphotodiode need not be positioned at an exact angle with respect to theblood flow tube. No special optical cuvettes are required. The secondsensor 336 can interface directly with the transparent plastic tubing294. Similarly, the first sensor 334 can interface directly with thetransparent tubing 292.

In the illustrated embodiment, the wavelength 805 nm is selected, as itis an isobestic wavelength for red blood cells, meaning that lightabsorption by the red blood cells at this wavelength is independent ofoxygen saturation. Still, other wavelengths can be selected within theNIR spectrum.

In the illustrated embodiment, for a wavelength of 805 nm, the preferredset distance is 7.5 mm from the light source. The fixture 338, abovedescribed (see FIG. 18), facilitates the placement of the tube 294 inthe desired relation to the light source and the reflected lightdetector of the second sensor 336. The fixture 338 also facilitates theplacement of the tube 292 in the desired relation to the light sourceand the reflected light detector of the first sensor 334.

Measurements at a distance greater than 7.5 mm can be made and will showa greater sensitivity to changes in the red blood cell hematocrit.However a lower signal to noise ratio will be encountered at thesegreater distances. Likewise, measurements at a distance closer to thelight source will show a greater signal to noise ratio, but will be lesssensitive to changes in the red blood cell hematocrit. The optimaldistance for a given wavelength in which a linear relationship betweenhematocrit and sensed intensity exists for a given hematocrit range canbe empirically determined.

The second sensor 336 detects absolute differences in the meantransmitted light intensity of the signal transmitted through the redblood cells in the red blood cell collection line. The detection moduleanalyzes these measured absolute differences in intensities, along withincreases in the standard deviation of the measured intensities, toreliably signal an under spill condition, as FIG. 20 shows.

At a given absolute hematocrit, G_(RBC) ^(λ) varies slightly from donorto donor, due to variations in the mean red blood cell volume and/or therefractive index difference between the plasma and red blood cells.Still, by measuring the reflected light from a sample of a given donor'sblood having a known hematocrit, G_(RBC) ^(λ) may be calibrated toyield, for that donor, an absolute measurement of the hematocrit of redblood cells exiting the processing chamber.

C. Pre-Processing Calibration of the Sensors

The first and second sensors 334 and 336 are calibrated during thesaline and blood prime phases of a given blood collection procedure, thedetails of which have already described.

During the saline prime stage, saline is conveyed into the bloodprocessing chamber 18 and out through the plasma collection line 292.During this time, the blood processing chamber 18 is rotated in cyclesbetween 0 RPM and 200 RPM, until air is purged from the chamber 18. Thespeed of rotation of the processing chamber 18 is then increased to fulloperational speed.

The blood prime stage follows, during which whole blood is introducedinto the processing chamber 18 at the desired whole blood flow rate(Q_(WB)). The flow rate of plasma from the processing chamber throughthe plasma collection line 292 is set at a fraction (e.g., 80%) of thedesired plasma flow rate (Q_(P)) from the processing chamber 18, topurge saline from the chamber 18. The purge of saline continues underthese conditions until the first sensor 334 optically senses thepresence of saline in the plasma collection line 292.

1. For Plasma Collection Procedures (Induced Under Spill)

If the procedure to be performed collects plasma for storage (e.g., thePlasma Collection Procedure or the Red Blood Cell/Plasma CollectionProcedure), an under spill condition is induced during calibration. Theunder spill condition is created by decreasing or stopping the flow ofplasma through the plasma collection line 292. This forces the buffycoat away from the low-G side of the chamber 18 (as FIG. 15C) to assurethat a flow of “clean” plasma exists in the plasma collection line 292,free or essentially free of platelets and leukocytes. The induced underspill allows the first sensor 334 to be calibrated and normalized withrespect to the physiologic color of the donor's plasma, taking intoaccount the donor's background lipid level, but without the presence ofplatelets or leukocytes. The first sensor 334 thereby possesses maximumsensitivity to changes brought about by the presence of platelets orleukocytes in the buffy coat, should an over spill subsequently occurduring processing.

Forcing an under spill condition also positions the interface close tothe high-G wall at the outset of blood processing. This creates aninitial offset condition on the high-G side of the chamber, to prolongthe ultimate development of an over spill condition as blood processingproceeds.

2. Red Blood Cell Collection Procedures

If a procedure is to be performed in which no plasma is to be collected(e.g., the Double Unit Red Blood Cell Collection Procedure), an underspill condition is not induced during the blood purge phase. This isbecause, in a red blood cell only collection procedure, the first sensor334 need only detect, during an over spill, the presence of red bloodcells in the plasma. The first sensor 334 does not need to be furthersensitized to detect platelets. Furthermore, in a red blood cell onlycollection procedure, it may be desirable to keep the interface as nearthe low-G wall as possible. The desired condition allows the buffy coatto be returned to the donor with the plasma and maximizes the hematocritof the red blood cells collected.

D. Blood Cell Collection

1. Plasma Collection Procedures

In procedures where plasma is collected (e.g., the Plasma CollectionProcedure or the Red Blood Cell/Plasma Collection Procedure), Q_(P) isset at Q_(P(Ideal)), which is an empirically determined plasma flow ratethat allows the system to maintain a steady state collection condition,with no underspills and no overspills.

Q_(P(Ideal)) (in grams/ml) is a function of the anticogulated wholeblood inlet flow rate Q_(WB), the anticoagulant whole blood inlethematocrit HCT_(WB), and the red blood cell exit hematocrit HCT_(RBC)(as estimated or measured), expressed as follows:

$Q_{P{({Ideal})}} = \left( {\rho_{Plasma}Q_{WB}*\frac{\left( {1 - {HCT}_{WB}} \right) - \left\lbrack {\frac{\rho_{WB}}{\rho_{RBC}}\left( {1 - {HCT}_{RBC}} \right)} \right\rbrack}{\left( {1 - \frac{\rho_{Plasma}}{\rho_{RBC}}} \right)\left( {1 - {HCT}_{RBC}} \right)}} \right.$

where:

ρ_(Plasma) is the density of plasma (in g/ml)=1.03

ρ_(WB) is the density of whole blood (in g/ml)=1.05

ρ_(RBC) is the density of red blood cells=1.08

Q_(WB) is set to the desired whole blood inlet flow rate for plasmacollection, which, for a plasma only collection procedure, is generallyabout 70 ml/min. For a red blood cell/plasma collection procedure,Q_(WB) is set at about 50 ml/min, thereby providing packed red bloodcells with a higher hematocrit than in a traditional plasma collectionprocedure.

The system controller 16 maintains the pump settings until the desiredplasma collection volume is achieved, unless an under spill condition oran over spill condition is detected.

If set Q_(P) is too high for the actual blood separation conditions, or,if due to the physiology of the donor, the buffy coat volume is larger(i.e., “thicker”) than expected, the first sensor 334 will detect thepresence of platelets or leukocytes, or both in the plasma, indicatingan over spill condition.

In response to an over spill condition caused by a high Q_(P), thesystem controller 16 terminates operation of the plasma collection pumpPP2, while keeping set Q_(WB) unchanged. In response to an over spillcondition caused by a high volume buffy coat, the system controller 16terminates operation of the plasma collection pump PP2, until an underspill condition is detected by the red blood cell sensor 336. Thisserves to expel the buffy coat layer from the separation chamber throughthe red blood cell tube 294.

To carry out the over spill response, the blood processing circuit 46 isprogrammed to operate the in-process pump PP1 (i.e., drawing in throughthe valve V9 and expelling out of the valve V14), to draw whole bloodfrom the in-process container 312 into the processing chamber 18 at theset Q_(WB). Red blood cells exit the chamber 18 through the tube 294 forcollection in the collection container 308. The flow rate of red bloodcells directly depends upon the magnitude of Q_(WB).

During this time, the blood processing circuit 46 is also programmed tocease operation of the plasma pump PP2 for a preestablished time period(e.g., 20 seconds). This forces the interface back toward the middle ofthe separation chamber. After the preestablished time period, theoperation of the plasma pump PP2 is resumed, but at a low flow rate(e.g., 10 ml/min) for a short time period (e.g., 10 seconds). If thespill has been corrected, clean plasma will be detected by the firstsensor 334, and normal operation of the blood processing circuit 46 isresumed. If clean plasma is not sensed, indicating that the over spillhas not been corrected, the blood processing circuit 46 repeats theabove-described sequence.

The programming of the circuit to relieve an over spill condition issummarized in the following table.

TABLE Programming of Blood Processing Circuit To Relive an Over SpillCondition (Plasma Collection Procedures) V1 • V2 ∘ V3 • V4 • V5 ∘ V6 •V7 • V8 • V9 •/∘ Pump In V10 • V11 • V12 • V13 • V14 •/∘ Pump Out V15 •V16 • V17 • V18 • V19 • V20 • V21 • V22 • V23 • PP1 □ PP2 ▪ PP3 ▪ PP4 ▪Caption: ∘ denotes an open valve; • denotes a closed valve; ∘/• denotesa valve opening and closing during a pumping sequence; ▪ denotes an idlepump station (not in use); and □ denotes a pump station in use.

Upon correction of an over spill condition, the controller 16 returnsthe blood processing circuit 46 to resume normal blood processing, butapplies a percent reduction factor (% RF) to the Q_(P) set at the timethe over spill condition was initially sensed. The reduction factor (%RF) is a function of the time between over spills, i.e., % RF increasesas the frequency of over spills increases, and vice versa.

If set Q_(P) is too low, the second sensor 336 will detect a decrease inthe red blood cell hematocrit below a set level, which indicates anunder spill condition.

In response to an under spill condition, the system controller 16 resetsQ_(P) close to the set Q_(WB). As processing continues, the interfacewill, in time, move back toward the low-G wall. The controller 16maintains these settings until the second sensor 336 detects a red bloodcell hematocrit above the desired set level. At this time, thecontroller 16 applies a percent enlargement factor (% EF) to the Q_(P)set at the time the under spill condition was initially sensed. Theenlargement factor (% EF) is a function of the time between underspills, i.e., % EF increases as the frequency of under spills increases.

Should the controller 16 be unable to correct a given under or overspill condition after multiple attempts (e.g., three attempts), an alarmis commanded.

2. Red Blood Cell Only Collection Procedures

In procedures where, only red blood cells and no plasma is collected(e.g., the Double Unit Red Blood Cell Collection Procedure), Q_(P) isset to no greater than Q_(P(Ideal)), and Q_(WB) is set to the desiredwhole blood inlet flow rate into the processing chamber 18 for theprocedure, which is generally about 50 ml/min for a double unit redblood cell collection procedure.

It may be desired during a double unit red blood cell collectionprocedure that over spills occur frequently. This maximizes thehematocrit of the red blood cells for collection and returns the buffycoat to the donor with the plasma. Q_(P) is increased over time if overspills occur at less than a set frequency. Likewise, Q_(P) is decreasedover time if over spills occur above the set frequency. However, toavoid an undesirably high hematocrit, it may be just as desirable tooperate at Q_(P(Ideal)).

The system controller 16 controls the pump settings in this way untilthe desired red blood cell collection volume is achieved, taking care ofunder spills or over spills as they occur.

The first sensor 334 detects an over spill by the presence of red bloodcells in the plasma. In response to an over spill condition, the systemcontroller 16 terminates operation of the plasma collection pump to drawplasma from the processing chamber, while keeping the set Q_(WB)unchanged.

To implement the over spill response, the blood processing circuit 46 isprogrammed (through the selective application of pressure to the valvesand pump stations) to operate the plasma pump PP2 and in-process pumpPP1 in the manner set forth in the immediately preceding Table. The redblood cells detected in the tube 292 are thereby returned to theprocessing chamber 18, and are thereby prevented from entering theplasma collection container 304.

The interface will, in time, move back toward the high-G wall. Thecontroller 16 maintains these settings until the second sensor 336detects a decrease in the red blood cell hematocrit below a set level,which indicates an under spill condition.

In response to an under spill condition, the system controller 16increases Q_(P) until the second sensor 336 detects a red blood cellhematocrit above the desired set level. At this time, the controller 16resets Q_(P) to the value at the time the most recent overspillcondition was sensed.

3. Buffy Coat Collection

If desired, an over spill condition can be periodically induced during agiven plasma collection procedure to collect the buffy coat in a buffycoat collection container 376 (see FIG. 10). As FIG. 10 shows, in theillustrated embodiment, the buffy coat collection container 376 iscoupled by tubing 378 to the buffy port P4 of the cassette 28. The buffycoat collection container 376 is suspended on a weigh scale 246, whichprovides output reflecting weight changes over time, from which thecontroller 16 derives the volume of buffy coat collected.

In this arrangement, when the induced over spill condition is detected,the blood processing circuit 46 is programmed (through the selectiveapplication of pressure to the valves and pump stations) to operate theplasma pump PP2 (i.e., drawing in through valve V12 and expelling outthrough valve V10, to draw plasma from the processing chamber 18 throughthe tube 378, while valves V4 and V6 are closed and valve V8 is opened.The buffy coat in the tube 378 is conveyed into the buffy coatcollection container 376. The blood processing circuit 46 is alsoprogrammed during this time to operate the in-process pump PP1 (i.e.,drawing in through the valve V9 and expelling out of the valve V14), todraw whole blood from the in-process container 312 into the processingchamber 18 at the set Q_(WB). Red blood cells exit the chamber 18through the tube 294 for collection in the collection container 308.

The programming of the circuit to relieve an over spill condition bycollecting the buffy coat in the buffy coat collection container 376 issummarized in the following table.

TABLE Programming of Blood Processing Circuit To Relive an Over SpillCondition by Collecting the Buffy Coat (Plasma Collection Procedures) V1• V2 • V3 • V4 ∘ V5 • V6 • V7 • V8 • V9 •/∘ Pump In V10 •/∘ Pump Out V11• V12 •/∘ Pump In V13 • V14 •/∘ Pump Out V15 • V16 • V17 • V18 • V19 •V20 • V21 • V22 • V23 • PP1 □ PP2 □ PP3 ▪ PP4 ▪ Caption: ∘ denotes anopen valve; • denotes a closed valve; ∘/• denotes a valve opening andclosing during a pumping sequence; ▪ denotes an idle pump station (notin use); and □ denotes a pump station in use.

After a prescribed volume of buffy coat is conveyed into the buffy coatcollection container 376 (as monitored by the weigh scale 246), normalblood processing conditions are resumed. Over spill conditions causingthe movement of the buffy coat into the tube 378 can be induced atprescribed intervals during the process period, until a desired buffycoat volume is collected in the buffy coat collection container.

VI. Another Programmable Blood Processing Circuit

A. Circuit Schematic

As previously mentioned, various configurations for the programmableblood processing circuit 46 are possible. FIG. 5 schematically shows onerepresentative configuration 46, the programmable features of which havebeen described. FIG. 34 shows another representative configuration of ablood processing circuit 46′ having comparable programmable features.

Like the circuit 46, the circuit 46′ includes several pump stationsPP(N), which are interconnected by a pattern of fluid flow paths F(N)through an array of in line valves V(N). The circuit is coupled to theremainder of the blood processing set by ports P(N).

The circuit 46′ includes a programmable network of flow paths F1 to F33.The circuit 46′ includes eleven universal ports P1 to P8 and P11 to P13and four universal pump stations PP1, PP2, PP3, and PP4. By selectiveoperation of the in line valves V1 to V21 and V23 to V25, any universalport P1 to P8 and P11 to P13 can be placed in flow communication withany universal pump station PP1, PP2, PP3, and PP4. By selectiveoperation of the universal valves, fluid flow can be directed throughany universal pump station in a forward direction or reverse directionbetween two valves, or an in-out direction through a single valve.

In the illustrated embodiment, the circuit 46′ also includes an isolatedflow path (comprising flow paths F9, F23, F24, and F10) with two portsP9 and P10 and one in line pump station PP5. The flow path is termed“isolated,” because it cannot be placed into direct flow communicationwith any other flow path in the circuit 46′ without exterior tubing. Byselective operation of the in line valves V21 and V22, fluid flow can bedirected through the pump station PP5 in a forward direction or reversedirection between two valves, or an in-out direction through a singlevalve.

Like circuit 46, the circuit 46′ can be programmed to assigned dedicatedpumping functions to the various pump stations. In a preferrredembodiment, the universal pump stations PP3 and PP4 in tandem serve as ageneral purpose, donor interface pump, regardless of the particularblood procedure performed. The dual donor interface pump stations PP3and PP4 in the circuit 46′ work in parallel. One pump station drawsfluid into its pump chamber, while the other pump station is expelsfluid from its pump chamber. The pump station PP3 and PP4 alternate drawand expel functions.

In a preferred arrangement, the draw cycle for the drawing pump stationis timed to be longer than the expel cycle for the expelling pumpstation. This provides a continuous flow of fluid on the inlet side ofthe pump stations and a pulsatile flow in the outlet side of the pumpstations. In one representative embodiment, the draw cycle is tenseconds, and the expel cycle is one second. The expelling pump stationperforms its one second cycle at the beginning of the draw cycle of thedrawing pump, and then rests for the remaining nine seconds of the drawcycle. The pump stations then switch draw and expel functions. Thiscreates a continuous inlet flow and a pulsatile outlet flow. Theprovision of two alternating pump stations PP3 and PP4 serves to reduceoverall processing time, as fluid is continuously conducted into adrawing pump station through out the procedure.

In this arrangement, the isolated pump station PP5 of the circuit 46′serves as a dedicated anticoagulant pump, like pump station PP4 in thecircuit 46, to draw anticoagulant from a source through the port P10 andto meter anticoagulant into the blood through port P9.

In this arrangement, as in the circuit 46, the universal pump stationPP1 serves, regardless of the particular blood processing procedureperformed, as a dedicated in-process whole blood pump, to convey wholeblood into the blood separator. As in the circuit 46, the dedicatedfunction of the pump station PP1 frees the donor interface pumps PP3 andPP4 from the added function of supplying whole blood to the bloodseparator. Thus, the in-process whole blood pump PP1 can maintain acontinuous supply of blood to the blood separator, while the donorinterface pumps PP3 and PP4 operate in tandem to simultaneously draw andreturn blood to the donor through the single phlebotomy needle. Thecircuit 46′ thus minimizes processing time.

In this arrangement, as in circuit 46, the universal pump station PP2 ofthe circuit 46′ serves, regardless of the particular blood processingprocedure performed, as a plasma pump, to convey plasma from the bloodseparator. As in the circuit 46, the ability to dedicate separatepumping functions in the circuit 46′ provides a continuous flow of bloodinto and out of the separator, as well as to and from the donor.

The circuit 46′ can be programmed to perform all the differentprocedures described above for the circuit 46. Depending upon theobjectives of the particular blood processing procedure, the circuit 46′can be programmed to retain all or some of the plasma for storage orfractionation purposes, or to return all or some of the plasma to thedonor. The circuit 46′ can be further programmed, depending upon theobjectives of the particular blood processing procedure, to retain allor some of the red blood cells for storage, or to return all or some ofthe red blood cells to the donor. The circuit 46′ can also beprogrammed, depending upon the objectives of the particular bloodprocessing procedure, to retain all or some of the buffy coat forstorage, or to return all or some of the buffy coat to the donor.

In a preferred embodiment (see FIG. 34), the circuit 46′ forms a part ofa universal set 264′, which is coupled to the ports P1 to P13.

More particularly, a donor tube 266′, with attached phlebotomy needle268′ is coupled to the port P8 of the circuit 46′. An anticoagulant tube270′, coupled to the phlebotomy needle 268′ is coupled to port P9. Acontainer 276′ holding anticoagulant is coupled via a tube 274′ to theport P10.

A container 280′ holding a red blood cell additive solution is coupledvia a tube 278′ to the port P3. A container 288′ holding saline iscoupled via a tube 284′ to the port P12. A storage container 289′ iscoupled via a tube 291′ to the port P13. An in-line leukocyte depletionfilter 293′ is carried by the tube 291′ between the port P13 and thestorage container 289′. The containers 276′, 280′, 288′, and 289′ can beintegrally attached to the ports or can be attached at the time of usethrough a suitable sterile connection, to thereby maintain a sterile,closed blood processing environment.

Tubes 290′, 292′, and 294′, extend to an umbilicus 296′ which is coupledto the processing chamber 18′. The tubes 290′, 292′, and 294 arecoupled, respectively, to the ports P5, P6, and P7. The tube 290′conveys whole blood into the processing chamber 18 under the operationof the in-process pump station PP1. The tube 292′ conveys plasma fromthe processing chamber 18′ under the operation of the plasma pumpchamber PP2. The tube 294′ conveys red blood cells from processingchamber 18′.

A plasma collection container 304′ is coupled by a tube 302′ to the portP3. The collection container 304′ is intended, in use, to serve as areservoir for plasma during processing.

A red blood cell collection container 308′ is coupled by a tube 306′ tothe port P2. The collection container 308′ is intended, in use, toreceive a unit of red blood cells for storage.

A buffy coat collection container 376′ is coupled by a tube 377′ to theport P4. The container 376′ is intended, in use, to receive a volume ofbuffy coat for storage.

A whole blood reservoir 312′ is coupled by a tube 310′ to the port P1.The collection container 312′ is intended, in use, to receive wholeblood during operation of the donor interface pumps PP3 and PP4, toserve as a reservoir for whole blood during processing. It can alsoserve to receive a second unit of red blood cells for storage.

B. The Cassette

As FIGS. 35 and 36 show, the programmable fluid circuit 46′ can beimplemented as an injection molded, pneumatically controlled cassette28′. The cassette 28′ interacts with the pneumatic pump and valvestation 30, as previously described, to provide the same centralized,programmable, integrated platform as the cassette 28.

FIGS. 35 and 36 show the cassette 28′ in which the fluid circuit 46′(schematically shown in FIG. 34) is implemented. As previously describedfor the cassette 28, an array of interior wells, cavities, and channelsare formed on both the front and back sides 190′ and 192′ of thecassette body 188′, to define the pump stations PP1 to PP5, valvestations V1 to V25, and flow paths F1 to F33 shown schematically in FIG.34. In FIG. 36, the flow paths F1 to F33, are shaded to facilitate theirviewing. Flexible diaphragms 194′ and 196′ overlay the front and backsides 190′ and 192′ of the cassette body 188′, resting against theupstanding peripheral edges surrounding the pump stations PP1 to PP5,valves V1 to V25, and flow paths F1 to F33. The pre-molded ports P1 toP13 extend out along two side edges of the cassette body 188′.

The cassette 28′ is vertically mounted for use in the pump and valvestation 30 in the same fashion shown in FIG. 2. In this orientation(which Fog. 36 shows), the side 192′ faces outward, ports P8 to P13 facedownward, and the ports P1 to P7 are vertically stacked one above theother and face inward.

As previously described, localized application by the pump and valvestation 30 of positive and negative fluid pressures upon the diaphragm194′ serves to flex the diaphragm to close and open the valve stationsV1 to V 25 or to expel and draw liquid out of the pump stations PP1 toPP5.

An additional interior cavity 200′ is provided in the back side 192′ ofthe cassette body 188′. The cavity 200′ forms a station that holds ablood filter material to remove clots and cellular aggregations that canform during blood processing. As shown schematically in FIG. 34, thecavity 200′ is placed in the circuit 46′ between the port P8 and thedonor interface pump stations PP3 and PP4, so that blood returned to thedonor passes through the filter. Return blood flow enters the cavity200′ through flow path F27 and exits the cavity 200′ through flow pathF8. The cavity 200′ also serves to trap air in the flow path to and fromthe donor.

Another interior cavity 201′ (see FIG. 35) is also provided in the backside 192′ of the cassette body 188′. The cavity 201′ is placed in thecircuit 46′ between the port P5 and the valve V16 of the in-processpumping station PP1. Blood enters the cavity 201′ from flow path F16through opening 203′ and exits the cavity 201′ into flow path F5 throughopening 205′ The cavity 201′ serves as another air trap within thecassette body 188′ in the flow path serving the separation chamber 26′.The cavity 201′ also serves as a capacitor to dampen the pulsatile pumpstrokes of the in-process pump PP1 serving the separation chamber.

C. Associated Pneumatic Manifold Assembly

FIG. 43 shows a pneumatic manifold assembly 226′ that can be used inassociation with the cassette 28′, to supply positive and negativepneumatic pressures to convey fluid through the cassette 28′. The frontside 194′ of the diaphragm is held in intimate engagement against themanifold assembly 226′ when the door 32 of the pump station 20 is closedand bladder 314 inflated. The manifold assembly 226′, under the controlof the controller 16, selectively distributes the different pressure andvacuum levels to the pump and valve actuators PA(N) and VA(N) of thecassette 28′. These levels of pressure and vacuum are systematicallyapplied to the cassette 28′, to route blood and processing liquids.Under the control of a controller 16, the manifold assembly 226 alsodistributes pressure levels to the door bladder 314 (already described),as well as to a donor pressure cuff (also already described) and to adonor line occluder 320 (also already described). The manifold assembly226′ for the cassette 28′ shown in FIG. 43 shares many attributes withthe manifold assembly 226 previously described for the cassette 28, asshown in FIG. 12.

Like the manifold assembly 226, the manifold assembly 226′ is coupled toa pneumatic pressure source 234′, which is carried inside the lid 40behind the manifold assembly 226′. As in manifold assembly 226, thepressure source 234′ for the manifold assembly 226 comprises twocompressors C1′ and C2′, although one or several dual-head compressorscould be used as well. Compressor C1 supplies negative pressure throughthe manifold 226′ to the cassette 281. The other compressor C2′ suppliespositive pressure through the manifold 226′ to the cassette 28.

As FIG. 43 shows, the manifold 226′ contains five pump actuators PA1 toPA4 and twenty-five valve actuators VA1 to VA25. The pump actuators PA1to PA5 and the valve actuators VA1 to VA25 are mutually oriented to forma mirror image of the pump stations PP1 to PP5 and valve stations V1 toV25 on the front side 190′ of the cassette 28′.

Like the manifold assembly 226, the manifold assembly 226′ shown in FIG.43 includes an array of solenoid actuated pneumatic valves, which arecoupled inline with the pump and valve actuators PA1 to PA5 and VA1 toVA25.

Like the manifold assembly 226, the manifold assembly 226′ maintainsseveral different pressure and vacuum conditions, under the control ofthe controller 16.

As previously described in connection with the manifold assembly 226,Phard, or Hard Pressure, and Pinpr, or In-Process Pressure are highpositive pressures (e.g., +500 mmHg) maintained by the manifold assembly226′ for closing the cassette valves V1 to V25 and to drive theexpression of liquid from the in-process pump PP1 and the plasma pumpPP2. As before explained, the magnitude of Pinpr must be sufficient toovercome a minimum pressure of approximately 300 mm Hg, which istypically present within the processing chamber 18. Pinpr and Phard areoperated at the highest pressure to ensure that upstream and downstreamvalves used in conjunction with pumping are not forced opened by thepressures applied to operate the pumps.

Pgen, or General Pressure (+300 mmHg), is applied to drive theexpression of liquid from the donor interface pumps PP3 and PP4 and theanticoagulant pump PP5.

Vhard, or Hard Vacuum (−350 mmHg), is the deepest vacuum applied in themanifold assembly 226′ to open cassette valves V1 to V25. Vgen, orGeneral Vacuum (−300 mmHg), is applied to drive the draw function ofeach of the pumps PP1 to PP5. Vgen is required to be less extreme thanVhard, to ensure that pumps PP1 to PP5 do not overwhelm upstream anddownstream cassette valves V1 to V25.

A main hard pressure line 322′ and a main vacuum line 324′ distributePhard and Vhard in the manifold assembly 324. The pressure and vacuumsources 234′ run continuously to supply Phard to the hard pressure line322′ and Vhard to the hard vacuum line 324′. A pressure sensor S2monitors Phard in the hard pressure line 322′. The sensor S2 opens andcloses the solenoid 38 to build Phard up to its maximum set value.

Similarly, a pressure sensor S6 in the hard vacuum line 324′ monitorsVhard. The sensor S6 controls a solenoid 43 to maintain Vhard as itsmaximum value.

A general pressure line 326′ branches from the hard pressure line 322′.A sensor S4 in the general pressure line 326′ monitors Pgen. The sensorS2 controls a solenoid 34 to maintain Pgen within its specified pressurerange.

A general vacuum line 330′ branches from the hard vacuum line 324′. Asensor S5 monitors Vgen in the general vacuum line 330′. The sensor S5controls a solenoid 45 to keep Vgen within its specified vacuum range.

In-line reservoirs R1 to R4 are provided in the hard pressure line 322,the general pressure line 326′, the hard vacuum line 324′, and thegeneral vacuum line 330′. The reservoirs R1 to R4 assure that theconstant pressure and vacuum adjustments as above described are smoothand predictable.

The solenoids 32 and 43 provide a vent for the pressures and vacuums,respectively, upon procedure completion.

The solenoids 41, 2, 46, and 47 provide the capability to isolate thereservoirs R1 to R4 from the air lines that supply vacuum and pressureto the pump and valve actuators. This provides for much quickerpressure/vacuum decay feedback, so that testing of cassette/manifoldassembly seal integrity can be accomplished.

The solenoids 1 to 25 provide Phard or Vhard to drive the valveactuators VA1 to V25. The solenoids 27 and 28 provide Pinpr and Vgen todrive the in-process and plasma pumps PP1 and PP2. The solenoids 30 and31 provide Pgen and Vgen to drive the donor interface pumps actuatorsPA3 and PA4. The solenoid 29 provides Pgen and Vgen to drive the AC pumpactuator PP5.

The solenoid 35 provides isolation of the door bladder 314 from the hardpressure line 322′ during the procedure. A sensor S1 monitors Pdoor andcontrol the solenoid 35 to keep the pressure within its specified range.

The solenoid 40 provides Phard to open the safety occluder valve 320′.Any error modes that might endanger the donor will relax (vent) thesolenoid 40 to close the occluder 320′ and isolate the donor. Similarly,any loss of power will relax the solenoid 40 and isolate the donor.

The sensor S3 monitors Pcuff and communicates with solenoids 36 (forincreases in pressure) and solenoid 37 (for venting) to maintain thedonor cuff within its specified ranges during the procedure.

As before explained, any solenoid can be operated in “normally open”mode or can be re-routed pneumatically to be operated in a “normallyclosed” mode, and vice versa.

D. Exemplary Pumping Functions

Based upon the foregoing description of the programming of the fluidcircuit 46 implemented by the cassette 28, one can likewise program thefluid circuit 46′ implemented by the cassette 28′ to perform all thevarious blood process functions already described. Certain pumpingfunctions for the fluid circuit 46′, common to various blood processingprocedures, will be described by way of example.

1. Whole Blood Flow to the In-Process Container

In a first phase of a given blood collection cycle, the blood processingcircuit 46′ is programmed (through the selective application of pressureto the valves and pump stations of the cassette 28′) to jointly operatethe donor interface pumps PP3 and PP4 to transfer anticoagulated wholeblood into the in-process container 312′ prior to separation.

In a first phase (see FIG. 37A), the pump PP3 is operated in a tensecond draw cycle(i.e., in through valves V12 and V13, with valves V6,V14, V18, and V15 closed) in tandem with the anticoagulant pump PP5(i.e., in through valve V22 and out through valve V21) to drawanticoagulated blood through the donor tube 270 into the pump PP3. Atthe same time, the donor interface pump PP4 is operated in a one secondexpel cycle to expel (out through valve V7) anticoagulant blood from itschamber into the process container 312′ through flow paths F20 and F1(through opened valve V4).

At the end of the draw cycle for pump PP3 (see FIG. 37B), the bloodprocessing circuit 46′ is programmed to operate the donor interface pumpPP4 in a ten second draw cycle(i.e., in through valves V12 and V14, withvalves V13, V18, and V18 closed) in tandem with the anticoagulant pumpPP5 to draw anticoagulated blood through the donor tube 270 into thepump PP4. At the same time, the donor interface pump PP3 is operated ina one second expel cycle to expel (out through valve V6) anticoagulantblood from its chamber into the process container 312′ through the flowpaths F20 and F1 (through opened valve V4).

These alternating cycles continue until an incremental volume ofanticoagulated whole blood enters the in process container 312′, asmonitored by a weigh sensor. As FIG. 37C shows, the blood processingcircuit 46′ is programmed to operate the in-process pump station PP1(i.e., in through valve V1 and out through valve V16) and the plasmapump PP2 (i.e., in through valve V17 and out through valve V11, withvalve V9 opened and valve V10 closed) to convey anticoagulated wholeblood from the in-process container 312 into the processing chamber 18′for separation, while removing plasma into the plasma container 304(through opened valve V9) and red blood cells into the red blood cellcontainer 308 (through open valve V2), in the manner previouslydescribed with respect to the circuit 46. This phase continues until anincremental volume of plasma is collected in the plasma collectioncontainer 304 (as monitored by the weigh sensor) or until a targetedvolume of red blood cells is collected in the red blood cell collectioncontainer (as monitored by the weigh sensor). The donor interface pumpsPP3 and PP4 toggle to perform alternating draw and expel cycles asnecessary to keep the volume of anticoagulated whole blood in thein-process container 312′ between prescribed minimum and maximum levels,as blood processing proceeds.

2. Red Blood Cell Return with In-Line Addition of Saline

When it is desired to return red blood cells to the donor (see FIG.37D), the blood processing circuit 46′ is programmed to operate thedonor interface pump station PP3 in a ten second draw cycle(i.e., inthrough valve V6, with valves V13 and V7 closed) to draw red blood cellsfrom the red blood cell container 308′ into the pump PP3 (through openvalves V2, V3, and V5, valve V10 being closed). At the same time, thedonor interface pump PP4 is operated in a one second expel cycle toexpel (out through valves V14 and V18, with valves V12 and V21 closed)red blood cells from its chamber to the donor through the filter cavity200′.

At the end of the draw cycle for pump PP3 (see FIG. 37E), the bloodprocessing circuit 46′ is programmed to operate the donor interface pumpPP4 in a ten second draw cycle(i.e., in through valve V7, with valves V6and V14 closed) to draw red blood cells from the red blood cellcontainer 308′ into the pump PP4. At the same time, the donor interfacepump PP3 is operated in a one second expel cycle to expel (out throughvalves V13 and V18, with valve V12 closed) red blood cells from itschamber to the donor through the filter chamber 200′. These alternatingcycles continue until a desired volume of red blood cells are returnedto the donor.

Simultaneously, valves V24, V20, and V8 are opened, so that the drawingpump station PP3 or PP4 also draws saline from the saline container 288′for mixing with red blood cells drawn into the chamber. As beforeexplained, the in line mixing of saline with the red blood cells raisesthe saline temperature and improves donor comfort, while also loweringthe hematocrit of the red blood cells.

Simultaneously, the in-process pump PP1 is operated (i.e., in throughvalve V1 and out through valve V16) and the plasma pump PP2 (i.e., inthrough valve V17 and out through valve V11, with valve V9 open) toconvey anticoagulated whole blood from the in-process container 312 intothe processing chamber for separation, while removing plasma into theplasma container 304, in the manner previously described with respect tothe fluid circuit 46.

3. In-Line Addition of Red Blood Cell Additive Solution

In a blood processing procedure where red blood cells are collected forstorage (e.g., the Double Red Blood Cell Collection Procedure or the RedBlood Cell and Plasma Collection Procedure) the circuit 46′ isprogrammed to operate the donor interface pump station PP3 in a tensecond draw cycle(in through valves V15 and V13, with valve V23 openedand valves V8, V12 and V18 closed) to draw red blood cell storagesolution from the container 280′ into the pump PP3 (see FIG. 38A).Simultaneously, the circuit 46′ is programmed to operate the donorinterface pump station PP4 in a one second expel cycle (out throughvalve V7, with valves V14 and V18 closed) to expel red blood cellstorage solution to the container(s) where red blood cells reside (e.g.,the in-process container 312 (through open valve V4) or the red bloodcell collection container 308′ (through open valves V5, V3, and V2, withvalve V10 closed).

At the end of the draw cycle for pump PP3 (see FIG. 38B), the bloodprocessing circuit 46′ is programmed to operate the donor interface pumpPP4 in a ten second draw cycle (i.e., in through valve V14, with valvesV7, V18, V12, and V13 closed) to draw red blood cell storage solutionfrom the container 280′ into the pump PP4. At the same time, the donorinterface pump PP3 is operated in a one second expel cycle to expel (outthrough valve V6, with valves V13 and V12 closed) red blood cell storagesolution to the container(s) where red blood cells reside. Thesealternating cycles continue until a desired volume of red blood cellstorage solution is added to the red blood cells.

4. In-Line Leukocyte Depletion

Circuit 46′ provides the capability to conduct on-line depletion ofleukocytes from collected red blood cells. In this mode (see FIG. 39A),the circuit 46′ is programmed to operate the donor interface pumpstation PP3 in a ten second draw cycle(in through valve V6, with valvesV13 and V12 closed) to draw red blood cells from the container(s) wherered blood cells reside (e.g., the in-process container 312′ (throughopen valve V4) or the red blood cell collection container 308 (throughopen valves V5, V3, and V2, with valve V10 closed)into the pump PP3.Simultaneously, the circuit 46′ is programmed to operate the donorinterface pump station PP4 in a one second expel cycle (out throughvalve V14, with valves V18 and V8 closed and valves V15 and V25 opened)to expel red blood cells through tube 291′ through the in-line leukocytedepletion filter 293′ to the leukocyte-depleted red blood cell storagecontainer 289′.

At the end of the draw cycle for pump PP3 (see FIG. 39B), the bloodprocessing circuit 46′ is programmed to operate the donor interface pumpPP4 in a ten second draw cycle(i.e., in through valve V7, with valvesV14 and V18 closed) to draw red blood cells from the container 312′ or308′ into the pump PP4. At the same time, the donor interface pump PP3is operated in a one second expel cycle to expel (out through valve V13,with valve V12 closed and valves V15 and V25 opened) red blood cellsthrough tube 291′ through the in-line leukocyte depletion filter 293′ tothe leukocyte-depleted red blood cell storage container 289′. Thesealternating cycles continue until a desired volume of red blood cellsare transfered through the filter 293 into the container 289′.

5. Staged Buffy Coat Harvesting

In circuit 46 (see FIG. 5), buffy coat is collected through port P4,which is served by flow line F4, which branches from flow line F26,which conveys plasma from the plasma pump station PP2 to the plasmacollection container 304 (also see FIG. 10). In the circuit 46′ (seeFIG. 34), the buffy coat is collected through the port P4 from the flowpath F6 as controlled by valve V19. The buffy coat collection pathbypasses the plasma pump station PP2, keeping the plasma pump stationPP2 free of exposure to the buffy coat, thereby keeping the collectedplasma free of contamination by the buffy coat components.

During separation, the system controller (already described) maintainsthe buffy coat layer within the separation chamber 18′ at a distancespaced from the low-G wall, away from the plasma collection line 292(see FIG. 15A). This allows the buffy coat component to accumulateduring processing as plasma is conveyed by operation of the plasma pumpPP2 from the chamber into the plasma collection container 304′.

To collect the accumulated buffy coat component, the controller opensthe buffy coat collection valve V19, and closes the inlet valve V17 ofthe plasma pump station PP2 and the red blood cell collection valve V2.The in-process pump PP1 continues to operate, bringing whole blood intothe chamber 18′. The flow of whole blood into the chamber 18′ moves thebuffy coat to the low-G wall, inducing an over spill condition) (seeFIG. 15B). The buffy coat component enters the plasma collection line292′ and enters flow path F6 through the port P6. The circuit 46′conveys the buffy coat component in F6 through the opened valve V19directly into path F4 for passage through the port P4 into thecollection container 376′.

The valve V19 is closed when the sensing station 332 senses the presenceof red blood cells. The plasma pumping station PP2 can be temporarilyoperated in a reverse flow direction (in through the valve V11 and outthrough the valve V17, with valve V9 opened) to flow plasma from thecollection container 302′ through the tube 292′ toward the separationchamber, to flush resident red blood from the tube 292′ back into theseparation chamber. The controller can resume normal plasma and redblood cell collection, by opening the red blood cell collection valve V2and operating the plasma pumping station PP2 (in through valve V17 andout through valve V11) to resume the conveyance of plasma from theseparation chamber to the collection container 302′.

Over spill conditions causing the movement of the buffy coat forcollection can be induced at prescribed intervals during the processperiod, until a desired buffy coat volume is collected in the buffy coatcollection container.

6. Miscellaneous

As FIG. 43 shows in phantom lines, the manifold assembly 226′ caninclude an auxiliary pneumatic actuator A_(AUX) selectively applyP_(HARD) to the region of the flexible diaphragm that overlies theinterior cavity 201′ (see FIG. 35). As previously described, whole bloodexpelled by the pumping station PP1 (by application of P_(HARD) byactuator PA2), enters flow path F5 through openings 203′ and 205′ intothe processing chamber 18′. During the next subsequent stroke of thePP1, to draw whole blood into the pumping chamber PP1 by application ofVGEN by actuator PA2, residual whole blood residing in the cavity 201′is expelled into flow path F5 through opening 205′, and into theprocessing chamber 18′ by application of P_(HARD) by A_(AUX). The cavity201′ also serves as a capacitor to dampen the pulsatile pump strokes ofthe in-process pump PP1 serving the separation chamber 18′.

It is desirable to conduct seal integrity testing of the cassette 28′shown in FIGS. 35 and 36 prior to use. The integrity test determinesthat the pump and valve stations within the cassette 28′ functionwithout leaking. In this situation, it is desirable to isolate thecassette 28′ from the separation chamber 26′. Valves V19 and V16 (seeFIG. 34) in circuit 264′ provide isolation for the whole blood inlet andplasma lines 292′ and 296′ of the chamber 18′. To provide the capabilityof also isolating the red blood cell line 294′, an extra valve fluidactuated station V26 can be added in fluid flow path F7 serving port P7.As further shown in phantom lines in FIG. 43, an addition valve actuatorVA26 can be added to the manifold assembly 26′, to apply positivepressure to the valve V26, to close the valve V26 when isolation isrequired, and to apply negative pressure to the valve V26, to open thevalve when isolation is not required.

VII. Blood Separation Elements

A. Molded Processing Chamber

FIGS. 21 to 23 show an embodiment of the centrifugal processing chamber18, which can be used in association with the system 10 shown in FIG. 1.

In the illustrated embodiment, the processing chamber 18 is preformed ina desired shape and configuration, e.g., by injection molding, from arigid, biocompatible plastic material, such as a non-plasticized medicalgrade acrilonitrile-butadiene-styrene (ABS).

The preformed configuration of the chamber 18 includes a unitary, moldedbase 388. The base 388 includes a center hub 120. The hub 120 issurrounded radially by inside and outside annular walls 122 and 124 (seeFIGS. 21 and 23). Between them, the inside and outside annular walls 122and 124 define a circumferential blood separation channel 126. A moldedannular wall 148 closes the bottom of the channel 126 (see FIG. 22).

The top of the channel 126 is closed by a separately molded, flat lid150 (which is shown separated in FIG. 21 for the purpose ofillustration). During assembly, the lid 150 is secured to the top of thechamber 18, e.g., by use of a cylindrical sonic welding horn.

All contours, ports, channels, and walls that affect the bloodseparation process are preformed in the base 388 in a single, injectionmolded operation. Alternatively, the base 388 can be formed by separatemolded parts, either by nesting cup shaped subassemblies or twosymmetric halves.

The lid 150 comprises a simple flat part that can be easily welded tothe base 388. Because all features that affect the separation processare incorporated into one injection molded component, any tolerancedifferences between the base 388 and the lid 150 will not affect theseparation efficiencies of the chamber 18.

The contours, ports, channels, and walls that are preformed in the base388 can vary. In the embodiment shown in FIGS. 21 to 23,circumferentially spaced pairs of stiffening walls 128, 130, and 132emanate from the hub 120 to the inside annular wall 122. The stiffeningwalls 128, 130, 132 provide rigidity to the chamber 18.

As seen in FIG. 23, the inside annular wall 122 is open between one pair130 of the stiffening walls. The opposing stiffening walls form an openinterior region 134 in the hub 120, which communicates with the channel126. Blood and fluids are introduced from the umbilicus 296 into and outof the separation channel 126 through this region 134.

In this embodiment (as FIG. 23 shows), a molded interior wall 136 formedinside the region 134 extends entirely across the channel 126, joiningthe outside annular wall 124. The wall 136 forms a terminus in theseparation channel 126, which interrupts flow circumferentially alongthe channel 126 during separation.

Additional molded interior walls divide the region 124 into threepassages 142, 144, and 146. The passages 142, 144, and 146 extend fromthe hub 120 and communicate with the channel 126 on opposite sides ofthe terminus wall 136. Blood and other fluids are directed from the hub120 into and out of the channel 126 through these passages 142, 144, and146. As will be explained in greater detail later, the passages 142,144, and 146 can direct blood components into and out of the channel 126in various flow patterns.

The underside of the base 388 (see FIG. 22) includes a shaped receptacle179. Three preformed nipples 180 occupy the receptacle 179. Each nipple180 leads to one of the passages 142, 144, 146 on the opposite side ofthe base 388.

The far end of the umbilicus 296 includes a shaped mount 178 (see FIGS.24 and 24A). The mount 178 is shaped to correspond to the shape of thereceptacle 179. The mount 178 can thus be plugged into the receptacle179 (as FIG. 25 shows). The mount 178 includes interior lumens 398 (seeFIG. 24A), which slide over the nipples 180 in the hub 120, to couple,the umbilicus 296 in fluid communication with the channel 126.

Ribs 181 within the receptacle 179 (see FIG. 22) uniquely fit within akey way 183 formed on the mount 178 (see FIG. 24A). The unique fitbetween the ribs 181 and the key way 183 is arranged to require aparticular orientation for plugging the shaped mount 178 into the shapedreceptacle 179. In this way, a desired flow orientation among theumbilicus 296 and the passages 142, 144, and 146 is assured.

In the illustrated embodiment, the umbilicus 296 and mount 178 areformed from a material or materials that withstand the considerableflexing and twisting forces, to which the umbilicus 296 is subjectedduring use. For example, a Hytrel® polyester material can be used.

This material, while well suited for the umbilicus 296, is notcompatible with the ABS plastic material of the base 388, which isselected to provide a rigid, molded blood processing environment. Themount 178 thus cannot be attached by conventional by solvent bonding orultrasonic welding techniques to the receptacle 179.

In this arrangement (see FIGS. 24 and 25), the dimensions of the shapedreceptacle 179 and the shaped mount 178 are preferably selected toprovide a tight, dry press fit. In addition, a capturing piece 185,formed of ABS material (or another material compatible with the materialof the base 388), is preferably placed about the umbilicus 296 outsidethe receptacle in contact with the peripheral edges of the receptacle179. The capturing piece 185 is secured to the peripheral edges of thereceptacle 179, e.g., by swaging or ultrasonic welding techniques. Thecapturing piece 185 prevents inadvertent separation of the mount 178from the receptacle 181. In this way, the umbilicus 296 can beintegrally connected to the base 388 of the chamber 18, even thoughincompatible plastic materials are used.

The centrifuge station 20 (see FIGS. 26 to 28) includes a centrifugeassembly 48. The centrifuge assembly 48 is constructed to receive andsupport the molded processing chamber 18 for use.

As illustrated, the centrifuge assembly 48 includes a yoke 154 havingbottom, top, and side walls 156, 158, 160. The yoke 154 spins on abearing element 162 attached to the bottom wall 156. An electric drivemotor 164 is coupled via an axle to the bottom wall 156 of the collar154, to rotate the yoke 154 about an axis 64. In the illustratedembodiment, the axis 64 is tilted about fifteen degrees above thehorizontal plane of the base 38, although other angular orientations canbe used.

A rotor plate 166 spins within the yoke 154 about its own bearingelement 168, which is attached to the top wall 158 of the yoke 154. Therotor plate 166 spins about an axis that is generally aligned with theaxis of rotation 64 of the yoke 154.

The top of the processing chamber 18 includes an annular lip 380, towhich the lid 150 is secured. Gripping tabs 382 carried on the peripheryof the rotor plate 166 make snap-fit engagement with the lip 380, tosecure the processing chamber 18 on the rotor plate 166 for rotation.

A sheath 182 on the near end of the umbilicus 296 fits into a bracket184 in the centrifuge station 20. The bracket 184 holds the near end ofthe umbilicus 296 in a non-rotating stationary position aligned with themutually aligned rotational axes 64 of the yoke 154 and rotor plate 166.

An arm 186 protruding from either or both side walls 160 of the yoke 154contacts the mid portion of the umbilicus 296 during rotation of theyoke 154. Constrained by the bracket 184 at its near end and the chamber16 at its far end (where the mount 178 is secured inside the receptacle179), the umbilicus 296 twists about its own axis as it rotates aboutthe yoke axis 64. The twirling of the umbilicus 296 about its axis as itrotates at one omega with the yoke 154 imparts a two omega rotation tothe rotor plate 166, and thus to the processing chamber 18 itself.

The relative rotation of the yoke 154 at a one omega rotational speedand the rotor plate 166 at a two omega rotational speed, keeps theumbilicus 296 untwisted, avoiding the need for rotating seals. Theillustrated arrangement also allows a single drive motor 164 to impartrotation, through the umbilicus 296, to the mutually rotating yoke 154and rotor plate 166. Further details of this arrangement are disclosedin Brown et al U.S. Pat. No. 4,120,449, which is incorporated herein byreference.

Blood is introduced into and separated within the processing chamber 18as it rotates.

In one flow arrangement (see FIG. 29), as the processing chamber 18rotates (arrow R in FIG. 29), the umbilicus 296 conveys whole blood intothe channel 126 through the passage 146. The whole blood flows in thechannel 126 in the same direction as rotation (which is counterclockwisein FIG. 29). Alternatively, the chamber 18 can be rotated in a directionopposite to the circumferential flow of whole blood, i.e., clockwise.The whole blood separates as a result of centrifugal forces in themanner shown in FIG. 15A. Red blood cells are driven toward the high-Gwall 124, while lighter plasma constituent is displaced toward the low-Gwall 122. In this flow pattern, a dam 384 projects into the channel 126toward the high-G wall 124. The dam 384 prevents passage of plasma,while allowing passage of red blood cells into a channel 386 recessed inthe high-G wall 124. The channel 386 directs the red blood cells intothe umbilicus 296 through the radial passage 144. The plasma constituentis conveyed from the channel 126 through the radial passage 142 intoumbilicus 296.

Because the red blood cell exit channel 386 extends outside the high-gwall 124, being spaced further from the rotational axis than the high-gwall, the red blood cell exit channel 386 allows the positioning of theinterface between the red blood cells and the buffy coat very close tothe high-g wall 124 during blood processing, without spilling the buffycoat into the red blood cell collection passage 144 (creating an overspill condition). The recessed exit channel 386 thereby permits redblood cell yields to be maximized (in a red blood cell collectionprocedure) or an essentially platelet-free plasma to be collected (in aplasma collection procedure).

In an alternative flow arrangement (see FIG. 30), the umbilicus 296conveys whole blood into the channel 126 through the passage 142. Theprocessing chamber 18 rotates (arrow R in FIG. 30) in the same directionas whole blood flow (which is clockwise in FIG. 30). Alternatively, thechamber 18 can be rotated in a direction opposite to the circumferentialflow of whole blood, i.e., clockwise. The whole blood separates as aresult of centrifugal forces in the manner shown in FIG. 15A. Red bloodcells are driven toward the high-G wall 124, while lighter plasmaconstituent is displaced toward the low-G wall 122.

In this flow pattern, the dam 384 (previously described) preventspassage of plasma, while allowing passage of red blood cells into therecessed channel 386. The channel 386 directs the red blood cells intothe umbilicus 296 through the radial passage 144. The plasma constituentis conveyed from the opposite end of the channel 126 through the radialpassage 146 into umbilicus 296.

In another alternative flow arrangement (see FIG. 31), the umbilicus 296conveys whole blood into the channel 126 through the passage 144. Theprocessing chamber 18 is rotated (arrow R in FIG. 31) in the samedirection as blood flow (which is clockwise in FIG. 31). Alternatively,the chamber 18 can be rotated in a direction opposite to thecircumferential flow of whole blood, i.e., counterclockwise. The wholeblood separates as a result of centrifugal forces in the manner shown inFIG. 15A. Red blood cells are driven toward the high-G wall 124, whilelighter plasma constituent is displaced toward the low-G wall 122.

In this flow pattern, a dam 385 at the opposite end of the channel 126prevents passage of plasma, while allowing passage of red blood cellsinto a recessed channel 387. The channel 387 directs the red blood cellsinto the umbilicus 296 through the radial passage 146. The plasmaconstituent is conveyed from the other end of the channel 126 throughthe radial passage 142 into umbilicus 296. In this arrangement, thepresence of the dam 384 and the recessed passage 386 (previouslydescribed) separates incoming whole blood flow (in passageway 144) fromoutgoing plasma flow (in passageway 142). This flow arrangement makespossible the collection of platelet-rich plasma, if desired.

In another alternative flow arrangement (see FIG. 32), the passage 144extends from the hub 120 into the channel 126 in a direction differentthan the passages 142 and 146. In this arrangement, the terminus wall136 separates the passages 142 and 146, and the passage 144 communicateswith the channel 126 at a location that lays between the passages 142and 146. In this arrangement, the umbilicus 296 conveys whole blood intothe channel 126 through the passage 146. The processing chamber 18 isrotated (arrow R in FIG. 32) in the same direction as blood flow (whichis clockwise in FIG. 32). Alternatively, the chamber 18 can be rotatedin a direction opposite to the circumferential flow of whole blood,i.e., counterclockwise. The whole blood separates as a result ofcentrifugal forces in the manner shown in FIG. 15A. Red blood cells aredriven toward the high-G wall 124, while lighter plasma constituent isdisplaced toward the low-G wall 122.

In this flow pattern, the passage 144 conveys plasma from the channel126, while the passage 142 conveys red blood cells from the channel 126.! As previously mentioned, in any of the flow patterns shown in FIGS. 28to 32, the chamber 18 can be rotated in the same direction or in anopposite direction to circumferential flow of whole blood in the channel126. Blood separation as described will occur in either circumstance.Nevertheless, it has been discovered that, rotating the chamber 18 inthe same direction as the flow of whole blood in the channel 126 duringseparation, appears to minimize disturbances due, e.g., Corioliseffects, resulting in increased separation efficiencies.

EXAMPLE

Whole blood was separated during various experiments into red bloodcells and plasma in processing chambers 18 like that shown in FIG. 28.In one chamber (which will be called Chamber 1), whole bloodcircumferentially flowed in the channel 126 in the same direction as thechamber 18 was rotated (i.e., the chamber 18 was rotated in acounterclockwise direction). In the other chamber 18 (which will becalled Chamber 2), whole blood circumferentially flowed in the channel126 in a direction opposite to chamber rotation (i.e., the chamber 18was rotated in a clockwise direction).

The average hematocrit for red blood cells collected were measured forvarious blood volume samples, processed at different combinations ofwhole blood inlet flow rates and plasma outlet flow rates. The followingTables summarize the results for the various experiments.

TABLE 1 (Flow in the Same Direction as Rotation) Number of Blood AverageHematocrit of Samples Average Whole Blood Red Blood Cells ProcessedHematocrit (%) Collected 7 45.4 74.8 4 40 78.8

TABLE 2 (Flow in the Opposite Direction as Rotation) Number of BloodAverage Hematocrit of Samples Average Whole Blood Red Blood CellsProcessed Hematocrit (%) Collected 3 43.5 55.5 2 42.25 58.25

Tables 1 and 2 show that, when blood flow in the chamber is in the samedirection as rotation, the hematocrit of red blood cells is greater thanwhen blood flow is in the opposite direction. A greater yield of redblood cells also means a greater yield of plasma during the procedure.

FIG. 33 shows a chamber 18′ having a unitary molded base 388′ like thatshown in FIGS. 21 to 23, but in which two flow paths 126′ and 390 areformed. The flow paths 126′ and 390 are shown to be concentric, but theyneed not be. The chamber 18′ shares many other structural features incommon with the chamber 18 shown in FIG. 23. Common structural featuresare identified by the same reference number marked with an asterisk.

The base 388′ includes a center hub 120′ which is surrounded radially bythe inside and outside annular walls 122′ and 124′, defining betweenthem the circumferential blood separation channel 126′. In thisembodiment, a second inside annular wall 392 radially surrounds the hub120′. The second circumferential blood separation channel 390 is definedbetween the inside annular walls 122′ and 392. This construction formsthe concentric outside and inside separation channels 126′ and 390.

An interruption 394 in the annular wall 122′ adjacent to the dam 384′establishes flow communication between the outside channel 126′ and theinside channel 390. An interior wall 396 blocks flow communicationbetween the channels 126′ and 390 at their opposite ends.

As the processing chamber 18′ rotates (arrow R in FIG. 33), theumbilicus 296 conveys whole blood into the outside channel 126′ throughthe passage 144′. The whole blood flows in the channel 126′ in the samedirection as rotation (which is counterclockwise in FIG. 33).Alternatively, the chamber 18′ can be rotated in a direction opposite tothe circumferential flow of whole blood, i.e., clockwise. The wholeblood separates in the outside channel 126′ as a result of centrifugalforces in the manner shown in FIG. 15A. Red blood cells are driventoward the high-G wall 124′, while lighter plasma constituent isdisplaced toward the low-G wall 122′.

As previously described, the dam 384′ prevents passage of plasma, whileallowing passage of red blood cells into a channel 386′ recessed in thehigh-G wall 124′. The channel 386′ directs the red blood cells into theumbilicus 296 through the radial passage 142′. The plasma constituent isconveyed from the channel 126′ through the interruption 394 into theinside separation channel 390.

The plasma flows circumferentially flow through the inside channel 390in a direction opposite to the whole blood in the outside channel 126′.Platelets remaining in the plasma migrate in response to centrifugalforces against the annular wall 124′. The channel 390 directs the plasmaconstituent to the same end of the chamber 18′ where whole blood isinitially introduced. The plasma constituent is conveyed from thechannel 390 by the passage 146′.

VIII. Other Blood Processing Functions

The many features of the invention have been demonstrated by describingtheir use in separating whole blood into component parts for storage andblood component therapy. This is because the invention is well adaptedfor use in carrying out these blood processing procedures. It should beappreciated, however, that the features of the invention equally lendthemselves to use in other blood processing procedures.

For example, the systems and methods described, which make use of aprogrammable cassette in association with a blood processing chamber,can be used for the purpose of washing or salvaging blood cells duringsurgery, or for the purpose of conducting therapeutic plasma exchange,or in any other procedure where blood is circulated in an extracorporealpath for treatment.

Features of the invention are set forth in the following claims.

1. A method for centrifugally separating whole blood into red bloodcells and a plasma constituent comprising the steps of rotating aseparation zone about a rotational axis, the rotating separation zonehaving radially spaced apart walls with a high-G side and a low-G sidelocated closer to the rotational axis than the high-G side, the spacedapart walls defining a blood flow path that extends circumferentiallyabout the rotation axis, the rotating separation zone including an entryregion where whole blood enters the rotating separation zone to beginseparation and a terminal wall that is circumferentially spaced from theentry region, where flow is halted, directing whole blood into therotating separation zone through a first path adjacent the entry region,to begin separation of the whole blood into red blood cells toward thehigh-G side and plasma constituent toward the low-G side, directing redblood cells separated in the separation zone in a circumferential flowdirection toward the terminal wall, and directing separated red bloodcells from the rotating separation zone through a second path thatcommunicates with the separation zone adjacent the terminal wall suchthat substantial plasma constituent can not flow circumferentially pastor into the second path, the second path including a portion that isrecessed into the high-G wall.
 2. A method according to claim 1 furtherincluding the step of directing separated plasma constituent from therotating separation zone through a third path.
 3. A method according toclaim 1 further including the step of directing separated plasmaconstituent from the rotating separation zone through a third path thatis spaced closer to the terminal wall than the third path is spaced fromthe first path.
 4. A method according to claim 1 further including thestep of directing separated plasma constituent from the rotatingseparation zone through a third path that is between the first path andthe second path.
 5. A method for centrifugally separating whole bloodinto red blood cells and a plasma constituent comprising the steps ofrotating a separation zone about a rotational axis, the rotatingseparation zone having radially spaced apart walls with a high-G sideand a low-G side located closer to the rotational axis than the high-Gside, a blood flow path that extends circumferentially about therotation axis, the rotating separation zone including an entry regionwhere whole blood enters the rotating separation zone to beginseparation and a terminal wall that is circumferentially spaced from theentry region, where flow is halted, directing whole blood into therotating separation zone through a first path adjacent the entry region,to begin separation of the whole blood into red blood cells toward thehigh-G side and plasma constituent toward the low-G side, directing redblood cells separated in the separation zone in a circumferential flowdirection toward the terminal wall, and directing separated red bloodcells from the rotating separation zone through a second path thatextends, at least in part, radially beyond the high-G wall of anupstream separation zone, said part of the second path including aportion which defines a constricted channel that allows red blood cellsto pass through the second path but substantially prevents the flow ofplasma through the second path.
 6. A method according to claim 5 furtherincluding the step of directing separated plasma constituent from therotating separation zone through a third path.
 7. A method according toclaim 5 further including the step of directing separated plasmaconstituent from the rotating separation zone through a third path thatis between the first path and the second path.
 8. A method forcentrifugally separating whole blood into red blood cells and a plasmaconstituent comprising the steps of: rotating a separation zone about arotational axis, the rotating separation zone having radially spacedapart walls with a high-G side and a low-G side located closer to therotational axis than the high-G side, the spaced apart walls defining ablood flow path that extends circumferentially about the rotation axis,the rotating separation zone including an entry region where whole bloodenters the rotating separation zone to begin separation and a terminalwall that is circumferentially spaced from the entry region, where flowis halted, directing whole blood into the rotating separation zonethrough a first path adjacent the entry region, to begin separation ofthe whole blood into red blood cells toward the high-G side and plasmaconstituent toward the low-G side, directing red blood cells separatedin the separation zone in a circumferential flow direction toward theterminal wall, and directing separated red blood cells from the rotatingseparation zone, in a circumferential flow direction, through a secondpath that extends, at least in part, radially beyond the high-G wall ofan upstream separation zone such that the red blood cells pass throughand beyond at least said part of second path and the second pathsubstantially prevents the flow of plasma therethrough.
 9. A methodaccording to claim 8 further including the step of directing separatedplasma constituent from the rotating separation zone through a thirdpath.
 10. A method according to claim 8 further including the step ofdirecting separated plasma constituent from the rotating separation zonethrough a third path that is between the first path and the second path.11. A method for centrifugally separating a biological fluid into atleast one higher density component and at least one lower densitycomponent, which includes plasma, the method comprising the steps of:rotating a separation zone about a rotational axis, the rotatingseparation zone having radially spaced apart walls with a high-G sideand a low-G side located closer to the rotational axis than the high-Gside, the spaced apart walls defining a blood flow path that extendscircumferentially about the rotational axis, the rotating separationzone including an entry region where the biological fluid enters therotating separation zone to begin separation and a terminal wall that iscircumferentially spaced from the entry region, flowing the biologicalfluid into this rotating separation zone through a first path adjacentthe entry region, to begin separation of the biological fluid into saidat least one higher density component toward the high-G side and said atleast one lower density component toward the low-G side, flowing said atleast one higher density component separated in the separation zone in acircumferential flow direction toward the terminal wall, removing saidat least one lower density component from the rotating separation zonethrough a second path that terminates at the low-G wall, and removingsaid at least one higher density component from the rotating separationzone through a third path located closer to the terminal wall than thesecond path, the third path including a portion that is recessed intothe high-G wall.
 12. A method according to claim 11 wherein thebiological fluid is whole blood.
 13. A method according to claim 11wherein said at least one higher density component is red blood cells.14. A method for centrifugally separating a biological fluid into atleast one higher density component and at least one lower densitycomponent, which includes plasma, the method comprising the steps of:rotating a separation zone about a rotational axis, the rotatingseparation zone having radially spaced apart walls with a high-G sideand a low-G side located closer to the rotational axis than the high-Gside, the spaced apart walls defining a blood flow path that extendscircumferentially about the rotational axis, the rotating separationzone including an entry region where the biological fluid enters therotating separation zone to begin separation and a terminal wall that iscircumferentially spaced from the entry region, flowing the biologicalfluid into this rotating separation zone through a first path adjacentthe entry region, to begin separation of the biological fluid into saidat least one higher density component toward the high-G side and said atleast one lower density component toward the low-G side, flowing said atleast one higher density component separated in the separation zone in acircumferential flow direction toward the terminal wall, and removingsaid at least one higher density component from the rotating separationzone through a second path that communicates with the separation zoneadjacent the terminal wall such that a substantial amount of said atleast one lower density component cannot flow circumferentially past orinto the second path, the second path including a portion that isrecessed into the high-G wall.
 15. A method according to claim 14wherein the biological fluid is whole blood.
 16. A method according toclaim 14 wherein said at least one higher density component is red bloodcells.